6 Review ISSN 2413-0516 J Contemp Med Sci | Vol. 7, No. 1, January-February 2021: 6 – 22 Introduction Viruses are microscopic particles ranging in size from 30 to 300 nm, lacking typical cellular structures. They are not able to reproduce outside the living host cell and are more like a large chemical compound. For this reason, they are also called compulsive intracellular parasites. Viruses can infect hosts ranging from bacteria to animals, plants to humans.1-3 Viruses rely on host cell surface receptors to enter the cell and employ host cellular machinery to replicate, assemble, and release new virus particles. Each virus has a specific mechanism to infect the host through the attachment of the virus to host cell membrane via binding of molecules of the outer surface of the virion to a receptor molecule on the host cell (protein or car- bohydrate); penetration and uncoating of the virus and subse- quent release of the virions into host cell; reverse transcription of viral RNA into DNA (i.e., Retroviruses); integration of the viral DNA into host cell genome; use of the cellular system for gene duplication and translation (i.e., human immunodefi- ciency virus (HIV)), or use of their system to produce mRNA coding for viral proteins (early genes); synthesis and assembly of nucleocapsids (late genes); release of the naked virions by cell lysis. Alternatively, viruses with envelopes can be released by a process known as budding, in which the nucleocapsid is wrapped by the membrane and pinched off4-8 (Fig. 1). As of now, viral infections are significant threats to human and animal health, imposing a tremendous economic burden. During the past two decades, the epidemic of Ebola virus, chikungunya virus, Zika virus, Yellow fever, the severe acute respiratory syndrome (SARS) virus and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), influenza, Nipah and henipaviral diseases, and Lassa fever raised signifi- cant challenges for public health authorities all over the world, highlighting the emerge of strategies to predict, prevent, or control the pathogens geographic spread, and the human-to- human transmission.9 In the 21st century, three members of the β-coronavirus genus caused deadly infections in humans. In 2002, the outbreak of SARS-CoV began in northern China and extended globally. After that, MERS-CoV spread out in the Middle East in 2012, and lately, SARS-CoV-2 (COVID-19) was reported on December 30, 2019, in Wuhan City, Hubei Province, China. SARS is an 80–160 nm single-stranded pos- itive RNA virus surrounded by a coat containing the E2 virus binding protein, the E1 matrix protein, and the nucleocapsid N protein. To date, no proven effective therapeutics or vac- cines exist for human coronaviruses infections.10 Current treatment options for coronavirus infections include medications such as Lopinavir/Ritonavir, Oseltamivir, Chloroquine, Hydroxychloroquine, Remdesivir, Favipiravir; nucleoside analogs; neuraminidase (NA) inhibitors; peptide (EK1); abidol; RNA synthesis inhibitors (such as TDF, 3TC); anti-inflammatory drugs (such as hormones and other mol- ecules); angiotensin-converting enzyme inhibitors or angio- tensin receptor blockers; and Chinese traditional medicine such ShuFengJieDu Capsules and Lianhuaqingwen Capsule. A patent review study offered that proteases inhibitors (since proteases are essential for viruses replication), monoclonal antibodies, and interferons (INFs) are definite targets for coronavirus infection treatment. This study also concluded that traditional formulations containing natural compounds might help to improve symptoms of infection such as fever, cough, sore throat, and shortness of breath.11,12 A recent A narrative review of herbal preparations against RNA viruses Eghbal Jasemi1¥, Saeideh Momtaz1,2,4¥*, Reza Ghaffarzadegan1, Amir Hossein Abdolghaffari3,2,4, Mohammad Abdollahi2 1 Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran, Iran. 2 Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. 3 Department of Toxicology and Pharmacology, School of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran. 4 Gastrointestinal Pharmacology Interest Group, Universal Scientific Education and Research Network, Tehran, Iran. ¥ Eghbal Jasemi and Saeideh Momtaz contributed equally in this work. *Correspondence to: Saeideh Momtaz (E-mail: saeideh58_momtaz@yahoo.com) (Submitted: 03 January 2021 – Revised version received: 28 January 2021 – Accepted: 08 February 2021 – Published online: 26 February 2021) Abstract Objective Although several therapeutics were designed to control infectious diseases, viral infections are still fatal. Currently, evidence extracted from in vivo, in vitro, and in silico studies support the antiviral activity of many herbs scientifically; however, the therapeutic potential of many other herbs is still unknown. Plants and their products may potentially control the propagation of viruses in a variety of conditions. Methods Data were extracted from PubMed, Scopus, Google Scholar, and Science Direct from 1983 to 2020. We gathered a list of plant extracts, phytochemicals, and herbal formulations that can inhibit RNA viral infections, mainly those are originated from the coronaviruses family. We also provided an overview of their inhibitory mechanism of actions. Results Plant families, including Lamiaceae, Asteraceae, and Myrtaceae, contain the highest number of species with anti-coronaviruses activities, respectively. Conclusions It can be suggested that the combination of these antiviral ingredients with each other, any synthetic compound, or already approved drugs or inhibitors can be a novel approach for antiviral therapies. Keywords viruses, coronaviruses, herbal extracts, phytochemicals, essential oils https://en.wikipedia.org/wiki/Lamiaceae 7 Review A narrative review of herbal preparations against RNA virusesSaeideh Momtaz et al. J Contemp Med Sci | Vol. 7, No. 1, January-February 2021: 6 – 22 study reported that some natural products such as lycorine, homoharringtonine, silvestrol, ouabain, tylophorine, and 7‐ methoxycryptopleurine may possess potential antiviral activ- ities at nanomolecular equivalent concentrations.13 Natural isolates or extracts such as scutellarein, silvestrol, tryptan- thrin, saikosaponin B2, lectins such as griffithsin, lycorine and polyphenolics including quercetin, myricetin, caffeic acid, psoralidin and isobavachalcone were also shown to be active against human coronaviruses.14 Given the significance of nat- ural products, particularly herbal preparations and phyto- chemicals, on viral infections, we tried to collect a list of plant species/bioactive components or antiviral herbal medicine formulations that are capable of combating viral infections in RNA viruses with emphasize on coronaviruses. We also pro- vided a summary of different types of viruses and the family of coronaviruses. Methods Study design Data were extracted from PubMed, Scopus, Google Scholar, and Science Direct, using the keywords “antiviral” OR “coro- navirus” OR “RNA virus” OR “herbals” OR “plant species” OR “herbal preparation” OR “herbs” OR “herbal formulation” in the title/summary and the keywords “plant, herb, phytochem- istry” in the whole text. The research results were included in the study, regardless of the time limitation. The final articles used in the current review were from 1983 to 2020. 32% of the references were from 2015 until 2020. Two persons inde- pendently evaluated studies and non-English and duplicates were excluded. We avoided studies on DNA viruses and focused on RNA viruses, specifically the coronavirus family. We also prioritized our work over studies that examined the antiviral mechanisms of plants and their derivatives. Data extraction A summary of information including the name of plants, essential oil, phytochemical compounds, and herbal formula- tion, method of study such as in vitro or in vivo, the model used in the assay, dosage of treatment, and finally the results of the study are presented in two tables. Study selection and characteristics Out of a total of 930 studies, 440 studies were deleted due to irrelevant title and abstract, 186 studies were excluded in repetitive, and 50 non-English studies were left out. In total, 22 studies remained to review the full text. A further 53 stud- ies were discontinued due to the irrelevance of criteria in this study. Types of viruses Viruses only reproduce within individual species. Therefore, to facilitate the study, they are divided into vertebrate viruses, invertebrate viruses, bacterial viruses (bacteriophage), and plant viruses, depending on the type of host. Virus families are classified by the suffix–viridae. Today, viruses are classified considering to three major characteristics: nature and struc- ture of the genome, viral symmetry nucleocapsids (icosahe- dral or helical), and general morphology. Nevertheless, other features are also used to viral classification: size, physiochemi- cal properties; mechanisms of gene expression and virus repli- cation; serological relationships; host and tissue susceptibility; and pathology. Vertebrate viruses are often classified accord- ing to their genomic content (DNA or RNA) (Table 1), single- or double-stranded, and linear or annular.15, 16 Double-stranded DNA (dsDNA) viruses There are many viruses with the dsDNA genome that infect mammals. They are divided into seven fami- lies: Hepadnaviridae, Polyomaviridae, Papillomaviridae, Adenoviridae, Herpesviridae, Poxviridae, and Asfarviridae. With the exception of the Poxviridae and Asfarviridae fami- lies, all families have members that can cause persistent infec- tion in humans or animals. Hepadenoviruses, polyomaviruses, papillomaviruses, and viral herpes are causally linked to human cancers. This suggests that dsDNA viruses have many ways of disrupting and influencing cell division. Many details of their reproduction cycle indicate that they evolved from ret- roviruses.17 Genomic content of these viruses enter the host cell nucleus and mimics the genome of the host cell. Typically, the viral genome is replicated from the host cell using a DNA polymerase, and the viral genome is transcribed from the host cell by RNA polymerase. The resulting transcripts are then Fig. 1 A schematic model of a coronavirus. 8 Review A narrative review of herbal preparations against RNA viruses Saeideh Momtaz et al. J Contemp Med Sci | Vol. 7, No. 1, January-February 2021: 6 – 22 transported to the cytoplasm and are replicated by the host cell ribosomes. Several replicated viral DNA molecules are converted to virions. Virions contain an entire virus particle, consisting of an outer protein shell called a capsid and an inner core of nucleic acid. Virions use the machinery of host cells to complete their life cycle and target other host cells, initiating new infection cycles.18 Single-stranded DNA (ssDNA) viruses This type of virus is often identified by the presence of two genes; a gene for viral nucleocapsid protein and another gene as a DNA replication enzyme. Once these viruses enter the cells, viral ssDNA converts to dsDNA using host cell DNA polymerase using the 3’ end of viral DNA as the base tem- plate for transcription, resulting in the production of viral pro- teins. Then replicated viral DNA is reconverted into an ssDNA genome, which later might form virions. Parvoviruses in dogs and cats belong to the ssDNA virus family.19-22 (+) Single-stranded RNA or (+) ssRNAs viruses This class is by far the largest group of viruses (i.e., many com- mon cold viruses and the poliovirus) and consequently has considerable variety in terms of size, structure, organization, and observed replication strategy. ssRNAs are also known as picornaviruses because they have small RNA genomes. The ssRNA genome can act as an mRNA molecule, thus called “+”. However, there are several common theme in genome orga- nization, particularly unsegmented and single open reading frame (ORF) genomes, where the proteolytic lysis of a long “polyprotein” leads to mature gene products. Non-segmented genomes with multiple ORFs require two rounds of translation or subgenomic mRNA to express structural and non-struc- tural proteins. According to this situation, there are multi-part genomes, each component has a single ORF. The virus genome in this class range in size from 5 kb (i.e., leviviruses) to 30 kb (i.e., coronaviruses).23 (-) Single-stranded RNA or (-) ssRNAviruses The negative-strand RNA viruses are a broad group of animal viruses that comprise several important human pathogens, including influenza, measles, mumps, rabies, respiratory syn- cytial, Ebola, and hantaviruses. All these viruses are envel- oped viruses whose genomes is consisted of either one (in paramyxoviruses, rhabdoviruses, filoviruses, and Borna- disease virus) or several (in orthomyxoviruses, bunyaviruses and arenaviruses) RNA segments. The virus carries its RNA- dependent RNA polymerase, which is responsible for the tran- scription and replication of the viral genome in the infected cell.24, 25 Double-stranded RNA (dsRNA) viruses Double-stranded RNA (dsRNA) molecules belong to a limited group of viruses such as Reoviruses with 10 different dsRNAs in their genomes.26 These viruses also contain the RNA repli- case enzyme as a part of the virus structure. This enzyme tran- scribes positive RNA strands and helps the virus to complete the steps of its replication cycle alone, such as rotaviruses.27, 28 (+) ssRNA retroviruses The retroviruses encompass a large family of infectious agents (Retroviridae) unified by a typical virion structure and mode of replication. Retroviruses genomes may serve as mRNA, consisting of a dimer of identical single-stranded RNA mol- ecules, each 7–10 kb in length. Viruses with genomes higher than 8 kb are those that have other genes in addition to Gag, Pol, and Env. They use an enzyme called reverse transcriptase, giving them the unique property of transcribing their RNA into DNA after entering a cell. Once the virus enters the cell, instead of the RNA (+) strand, the virion RNA is used as a template to create a DNA copy of the viral genome through a viral enzyme called reverse transcriptase. This viral DNA becomes integrated into the host-cell DNA. Such viral DNA is called a “provirus”, identical to the genes of host cells. This integrated provirus is transcribed into RNA (+) and is trans- ported to the cytoplasm to be utilized for the synthesis of viral proteins, or as a genome for new viruses. Retroviruses are in effect retrograde because the flow of genetic information is reversed compared with the normal pathway of molecular biosynthesis: DNA to RNA and then to protein. These viruses are referred to as Human Endogenous Retroviruses or HERVs. HIV is a retrovirus and a member of the lentivirus.29, 30 Approaches to counter virus infection should be adjusted according to the specific viral characteristics. To this end, today’s medicines hit targets that minimize the risk of disease by disrupting the vital functions of the virus. Table 2 provides a summary of current medications with their mechanism of action for viral infections. There are several therapeutic tar- gets for these drugs, which are also used to design new drugs. Considering the side effects of chemical drugs, the search for new drugs with similar properties and fewer side effects could fix a significant part of the health problems area. Coronaviruses; structure, genome, and lifecycle The family Coronaviridae includes the genus Coronavirus and Torovirus. Coronaviruses belong to the family Coronaviridae, suborder Cornidovirineae, order Nidovirales, and realm Riboviria. Coronaviruses are large enveloped positive-sense, ssRNA viruses of vertebrates by importance in medical and veterinary diseases.31 The same other RNA viruses, Table 1. Types of viruses, examples and their typical properties. Virus type Example Properties DNA viruses Poxviruses, Herpes, Adenoviruses, Papillomaviruses Contain mostly double-stranded DNA, a small number single- stranded DNA. DNA viruses enter the cell nucleus and direct the generation of new viruses RNA viruses Influenza, Measles, Mumps, Cold, Meningitis, Poliomyelitis, Retroviruses (AIDS, T-cell leukemia), Arenaviruses, Coronaviruses Contain largely ssRNA. RNA viruses do not enter the cell nucleus (except the influenza virus). RNA retroviruses use the viral reverse transcriptase to make a DNA copy of the viral RNA, which is then integrated into the host genome ssRNA, single-stranded RNA. 9 Review A narrative review of herbal preparations against RNA virusesSaeideh Momtaz et al. J Contemp Med Sci | Vol. 7, No. 1, January-February 2021: 6 – 22 coronaviruses are highly mutant. However, the mutation rate might be somewhat lower than other RNA viruses because of its genome-encoded exonuclease, enabling the viruses to become more virulent and to extend more efficiently through different hosts.32 Coronaviruses are likely to have a seasonal distribution and may cause asymptomatic as well as lower and upper respiratory tract infections.33 It has been reported that human coronaviruses can infect neurons since viral RNA has been detected in the brain of patients with multiple sclerosis.34 Interest in this family of viruses has increased in recent years due to the identification of a newly emerging coronavirus as the causative agent of SARS and MERS.35, 36 Until the appear- ance of SARS in 2003, only four human low-pathogenic; HCoV-OC43, HCoVHKU1, HCoV-NL63, and HCoV-229E, were recognized, of which types 229E and OC43 constitute a significant cause of the common cold and therefore were not high precedence for centralized research.37-39 Coronaviruses contain three significant proteins in their structure: the very large (200 K) glycoprotein S (spike) is the major inducer of neutralizing antibody, which forms the large (15–20 nm) peplomers in the virus envelope; an unusual transmembrane protein (M); and an internal phosphorylated nucleocapsid protein (N). Moreover, there is a tiny transmembrane protein E, and some coronaviruses contain another coat protein with hemagglutination and esterase (HE) functions.40, 41 Their 30-kb (+) ssRNA is the largest known RNA virus genome with G+C contents varying from 32% to 43%.42 The viral genome contains distinctive features, including a unique N-terminal fragment within the spike protein. SARS-CoV-2 binds to ACE2 (the angiotensin 2 converting enzyme) via its S protein and enables the virus to penetrate and infect cells. To complete the virus entrance into the cells, the S protein must be enzymatically prepared by a protease, for example, protease TMPRSS2 in the case of SARS-CoV and SARS- CoV-2. TMPRSS2 facilitates the linkage of the virus receptor (S protein) to its cellular ligand (ACE2)43, 44 (Fig. 1). Since the S glycoprotein is surface-exposed and mediates the virus entry into host cells, also, the ACE2 could mediate SARS-CoV-2 S-mediated entry into cells, they both are the main targets of ongoing vaccine and therapeutic design efforts and for neu- tralizing polyclonal antibodies upon infection.45 Within the host cell, the virus undergoes uncoating, and then the genome Table 2. Antiviral mechanisms of compounds as therapeutic targets in medical applications. Antiviral mechanism Target virus (es) Compounds approved Selected compounds in development for the indicated target virus Reference Virus adsorption inhibitors HIV, Herpesviruses (HSV), CMV, RSV, and other enveloped viruses - Polysulphates, polysulphonates, polycarboxylates, polyoxometalates, chicoric acid, zintevir, cosalane derivatives, negatively charged albumins 51-55 Viral DNA polymerase inhibitors HSV-1 & -2,VZV, CMV, EBV, HHV-6, -7, -8 Acyclovir, valaciclovir, ganciclovir, valganciclovir, penciclovir, famciclovir, brivudin, foscarnet Bicyclic furopyrimidine nucleoside analogues, A5021, cyclohexenylguanine 56-58 Reverse transcriptase HIV NRTIs: zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir NNRTIs: nevirapine, delavirdine, efavirenz Emtricitabine, amdoxovir Emivirine, UC781, DPC083, TMC125 (R165335) 59-63 Virus–cell fusion inhibitors HIV, RSV, and other paramyxoviruses - HIV: AMD3100, TAK779 and T20 derivatives 64-66 Acyclic nucleoside phosphonates DNA viruses (polyoma, papilloma-, herpes-, adeno- and poxviruses), HIV, HBV CMV: cidofovir HIV: tenofovir HBV: adefovir 67-69 Viral protease inhibitors HIV, herpesviruses, rhinoviruses, HCV HIV: saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir HIV: atazanavir, mozenavir, tipranavir Human rhinovirus: AG7088 70-74 Inhibitors of processes associated with viral RNA synthesis HIV, HCV - - 75 Viral neuraminidase inhibitors Influenza A and B virus Zanamivir, oseltamivir§ RWJ270201 76-79 IMP dehydrogenase inhibitors HCV, RSV Ribavirin Mycophenolic acid, EICAR, VX497 80-82 S-adenosylhomocysteine hydrolase (–) RNA hemorrhagic fever viruses (for example, Ebola) - - 83, 84 https://www.sciencedirect.com/topics/immunology-and-microbiology/neutralizing-antibody https://www.sciencedirect.com/topics/immunology-and-microbiology/virus-nucleocapsid 10 Review A narrative review of herbal preparations against RNA viruses Saeideh Momtaz et al. J Contemp Med Sci | Vol. 7, No. 1, January-February 2021: 6 – 22 is transcribed and translated. As mentioned earlier, the pos- itive-stranded viral RNA serves as mRNA for the translation of the two large ORFs (ORF 1a and 1b), each coding for the RNA polymerase units, depending on the RNA. Upon cleav- age, these proteins covert to the active RNA polymerase, forming a full-length complementary RNA (negative sense). Cytoplasmic membranes are the site of coronavirus repli- cation and transcription. These membranes modulate both continuous and discontinuous RNA synthesis through a viral replica, a large protein complex encoding the 20 kb replicase gene.46 Based on the genome size, numerous genetic recom- bination can happen between different but related coronavi- rus genomes, which is a critical mechanism for the genetic diversity of coronaviruses in nature.47 During maturation and assembly, protein S is co-translationally inserted into the rough endoplasmic reticulum (RER) and is glycosylated with N-linked glycans. Glycosylation is a crucial stage for protein S function and transportation. Protein S forms trimers before being exported from ER, and then interacts with proteins M and E to translocate to the site of virus assembly. SARS-CoV expresses another structural protein which is called 3a. This protein is associated with both the intracellular and plasma membranes, and can induce programmed cell death (apopto- sis). Protein S is crucial for virus entry, but not for its assem- bly48-50 (Fig. 2). Herbal preparations and antiviral mechanisms Medicinal herbs, especially those used in folk medicine, have been highly regarded in the treatment of viral diseases because they contain bioactive substances that can be used to produce antiviral drugs with minimal side effects. Several secondary plant metabolites such as essential oils, flavonoids, sapo- nins, tannins, alkaloids, lignans, terpenes, and phenolic acids shown significant antiviral activities against various viruses.85, 86 Indeed, those elements that interfere with certain stages of viral biosynthesis, for example, the replication cycle, are the best for clinical antiviral approaches. Low concentrations and minimum effects on host cell machinery are the main privi- leges of these drugs, which ultimately leads to cure of infected cells. On the other hand, virucidal drugs denature viral struc- tural proteins or glycoproteins, which results in a total loss of the infectivity of the viral particles. The therapeutic approach, as well as herbal derivatives, could apply different strategies to inhibit virus function. It is known that both protein and lipid–protein of capsids must protect the nucleic acid inside the virus from the harmful substances, and facilitate the sur- face absorption of the virion into the host cell. The invasion of a cell by a viral particle always depends on its specific and close connection to one of the surface components of the host cell’s plasma membrane.87 Some plants use this mechanism to abolish the virus entry into the host cell by blocking their attachments to the cell surface.88 Most RNA viruses propagate in the cytoplasm because they have all the enzymes needed for in their genome.89 This step may be a therapeutic target for some herbal compounds due to their inhibitory effects.90 The HIV protease enzyme is responsible for the proteolytic cleav- age between gag and gag-pol precursor polypeptide, which in turn converts them into functional forms and ensures the viral maturation and infectivity. The HIV polymerase inhibitors show their activity at the end of virus replication and therefore interfere with active virus formation functionally.91, 92 Many active plant compounds act as HIV protease inhibitors are shown in in-vitro assays.93 Besides, the HIV integrase enzyme performs two main functions: the entry of pre-viral complexes into the nuclear pores and then the integration of the viral DNA genome into the host cell chromosome.94 The effective- ness of some herbs in inhibiting this enzyme has reduced the proliferation of the HIV-1 virus.95 Some phytochemicals have been studied, and results indicated their efficiency in integrase activity.96 The influenza virus NA causes the release of the virus from the host cell surface by catalysis a breakdown in the silicic acid attached to glycoprotein and glycolipid.97, 98 The inhibition of this enzyme can be considered as one of the ther- apeutic targets in medicinal plant studies.99 It is well evidenced that many plants contain ribosome‐inactivating proteins (RIPs) with N-glycosidase activity that can affect ribosomal function through depurination of large ribosomal rRNAs in infected cell and Inhibition of viral protein synthesis. RIPs Fig. 2 A viral cycle of a coronavirus in the host cell. 11 Review A narrative review of herbal preparations against RNA virusesSaeideh Momtaz et al. J Contemp Med Sci | Vol. 7, No. 1, January-February 2021: 6 – 22 can inhibit viral mRNA and DNA replication. Depurination is defined as inactivation of ribosomes by removal of a specific adenine from the sarcin/ricin (S/R) loop of the large rRNA, thereby inhibiting translation. To date, RIPs were shown effec- tive against HIV, HBV, and HSV. For example, Trichosanthin (Trichosanthes kirilowii), PAP (Pokeweed americana), GAP31 (Gelonium multiflorum) and MAP30 (Momordica charantia) have been reported to inhibit HIV-1 replication in vitro.100, 101 In following sections, we prepared a list of herbal preparations, essential oils, and phytochemicals that were able to inhibit the activity of the coronaviruses family. Herbal extracts To date, numerous herbal preparations were investigated against various types of viruses. Table 3 represents plant spe- cies, and those were shown valid on coronaviruses. Morus spp. Antiviral properties of the leaves and the stem bark of the mulberry tree (Morus spp.) were evaluated in human corona- virus (HCoV 229E) in L-132 cells. It was shown that Morus spp. reduced the viral titer and the cytopathogenic effects. The hydroalcoholic extract of the leaves exhibited the highest antiviral activity. The inhibition percentage of viral infectivity ranged from 34% to 36% for the aqueous stem bark extracts and from 37% to 45% for the hydromethanolic stem bark extracts. In comparison, this inhibition ranged from 67% to 100% for the hydromethanolic extracts of leaves.102 Echinacea purpurea Antiviral potential of E. purpurea examined against HCoV 229E and the highly pathogenic MERS- and SARS-CoVs in vitro. HCoV-229E was irreversibly inactivated when exposed to Echinaforce (a commercial standardized extract of  E. pur- purea) at an IC50 of 3.2 µg/ml. Pre-treatment of cell lines had only a marginal effect on virus propagation at 50 µg/ml.103 Uvaria angolensis The methanolic extract of the stem bark of U. angolensis inhibited both the HIV-1 RNase H enzyme and the reverse transcriptase activities with IC50 values of 1.0  ±  0.2 and 0.62 ± 0.15 μg/mL, respectively. RDS1643 and Efavirenz were considered as control of RNase H inhibitor and reverse tran- scriptase, respectively. The IC50 values for RDS1643 were mea- sured as 2.7 ± 0.2 μg/mL.104 Pometia pinnata Leaf and bark of P. pinnata have traditionally been used to treat fever and fester. The ethanolic extracts of P. pinnata (Sapindaceae) leaves have shown one of the most potent inhib- itory activity against HIV-1 integrase in vitro with an IC50 value of 8.8 µg/mL. In this study, proanthocyanidin A2 was isolated as an anti-HIV-1 integrase compound, with an IC50 value of 30.1 µM.95 Anthemis hyalina Antimicrobial activities of different species in the genus of Anthemis have been documented. Treating HeLa CEACAM1 cells infected coronavirus MHV-A59 with the ethanoic extract of Anthemis hyaline decreased the proliferation and function of this virus. However, this herb has a positive effect on IL-8 secretion and expression of transient receptor potential pro- teins (TRP) family genes, and its primary role was reducing the viral load.105 Phyllanthus amarus The hydroalcoholic extract of P. amarus leaves inhibited the interaction of HIV-1 envelope gp120 protein with its CD40 cell receptor up to 50%. Inhibition of virus envelope protein gp120 binding to the cellular receptor CD4 was the primary mechanism underlying the blocked virus entry. The extract also showed an inhibitory effect on other enzymes of the virus, such as reverse transcriptase, integrase, and protease.106 Glycine max or Black soybean An aqueous/ethanol extract of black soybean inhibited respi- ratory tract viruses such as human adenovirus type 1, cox- sackie B1, and influenza A in Vero, HeLa, MDCK, and FL cell lines in a dose-dependent manner. Ethanolic extract from black soybean demonstrated dose-dependent inhibitory activ- ity against human adenovirus type 1 replication. The antivi- ral index was about 1.5 mg/ml, and significant activity was recorded at 3.5 mg/ml.107 Sambucus nigra In a placebo-controlled randomized, double-blind study, oral administration of elderberry (Sambucus nigra) extract was shown to be an effective, safe, and cost-saving healing agent in influenza patients. In this study, patients received 15 ml of elderberry syrup for 5 days, and they recorded their symptoms on a visual analog scale. Compared with placebo, respiratory influenza symptoms improved 4 days earlier, and their need for medication decreased.108 Geranium sanguineum Geranium sanguineum belonging to Geraniaceae is one of the medicinal plants rich in polyphenols, which reduces infec- tion of various types of influenza viruses (H7N1, H7N7, and H3N2) in chicken embryo fibroblasts, MDCK cell lines and ICR mice (10 mg/kg in mice). n-butanol/ethanol and the etha- nol/acetic acid fractions showed the highest antiviral effects in vitro and in vivo, respectively.109 Boehmeria nivea Boehmeria nivea root extract reduced Hepatitis B virus (HBV) replication in vitro (in HepG2 2.2.15 cell). Real-time PCR, Southern blot and Northern blot techniques were used in this study to assay viral gene expression and replication.110 Polygonum cuspidatum Different extracts of P. cuspidatum was shown to inhibit various viruses. This effect was associated with the pres- ence of a class of the chemical group called anthraquinones. Anthraquinones have been reported to possess antiviral and virucidal activities against various types of viruses. Ethanolic extract of P. cuspidatum inhibited the HBV replication in a dose-dependent manner in the stable HepG2 2.2.15 hepato- blastoma cell line.111 Guazuma ulmifolia G. ulmifolia, also known as mutamba, has therapeutic effects such as wound healing, antiulcerogenic, hypoglycemic and https://www.sciencedirect.com/topics/medicine-and-dentistry/echinacea-purpurea https://www.sciencedirect.com/topics/medicine-and-dentistry/echinacea-purpurea https://en.wikipedia.org/wiki/Geraniaceae 12 Review A narrative review of herbal preparations against RNA viruses Saeideh Momtaz et al. J Contemp Med Sci | Vol. 7, No. 1, January-February 2021: 6 – 22 Ta bl e 3. M ed ic in al p la nt s i nv es tig at ed a ga in st co ro na vi ru se s a nd re la te d vi ru se s. Sc ie nt ifi c n am e  Fa m ily M ec ha ni sm He rb al p ro du ct Ty pe o f st ud y Eff ec tiv e do sa ge Ce ll ty pe /a ni m al m od el Vi ru s Re fe re nc e M or us sp p. M or ac ea e In hi bi tio n of v ira l i nf ec tiv ity Le av es a nd s te m b ar k ex tr ac t In v itr o 5 µg /m L L- 13 2 co ro na vi ru s (H Co V 22 9E ) (1 02 ) Ec hi na ce a pu rp ur ea As te ra ce ae Vi ru ci da l a ct iv ity H er ba l e xt ra ct In v itr o 3. 2 µg /m l H uh -7 Ve ro A 9 M ER S- a nd S A RS - Co Vs 10 3 A nt he m is h ya lin a As te ra ce ae D ec re as e vi ru s lo ad a nd IL -8 de cr ea se T RP g en es e xp re ss io n Et ha no lic e xt ra ct In v itr o - H eL a ce ac am i Co ro na vi ru s M H V- A 59 10 5 Sa m bu cu s n ig ra Ad ox ac ea e Im pr ov e sy m pt om s an d ov er al l w el lb ei ng H er ba l e xt ra ct A C lin ic al tr ia l 15 m l o f s yr up fo ur tim es a d ay , f or 5  d ay s - In flu en za 10 8 U va ri a an go le ns is A nn on ac ea e H IV -1 R N as e H e nz ym e an d re ve rs e tr an sc rip ta se a ct iv ity M et ha no l s te m b ar k ex tr ac t In v itr o 1. 0  ±  0 .2 a nd 0. 62  ±  0 .1 5  μg /m L A 54 9 H IV -1 10 4 Po m et ia p in na ta Sa pi nd ac ea e Ac tiv ity a ga in st H IV -1 in te gr as e Et ha no l l ea ve s ex tr ac t In v itr o 8. 8 µg /m L - H IV -1 95 Bo eh m er ia n iv ea U rt ic ac ea e In hi bi t H BV D N A s ec re tio n in to su pe rn at an t Ro ot e xt ra ct In v itr o 10 m g/ L H ep G 2 2. 2. 15 hu m an he pa to bl as to m a H BV 11 0 Po ly go nu m c us pi da tu m Po ly go na ce ae In cr ea se e xp re ss io n of H Bs Ag de cr ea se H BV D N A in th e su sp en si on Et ha no lic e xt ra ct In v itr o 30 μ g/ m l H ep G 2 2. 2. 15 hu m an he pa to bl as to m a H BV 11 1 G ua zu m a ul m ifo lia M al va ce ae In hi bi te d re pl ic at io n bl oc k th e sy nt he si s of vi ra la nt ig en s H er ba l e xt ra ct In v itr o 5 m g/ m l H Ep -2 (h um an la ry nx c ar ci no m a) ce lls Po lio vi ru s- 1 & Bo vi ne H er pe sv iru s 11 2 O le a eu ro pa ea O le ac ea e D ec re as e VH SV ti te rs a nd v ira l pr ot ei n ac cu m ul at io n in hi bi ts re pl ic at io n m od ul at e ho st c el l g en e ex pr es si on p ro fil e Le af e xt ra ct In v itr o 0. 6– 1 m g/ m l Ep ith el io m a pa pu lo su m cy pr in id M T2 c el l l in e H em or rh ag ic se pt ic ae m ia v iru s (V H SV ) a nd H IV -1 11 4, 1 40 Ph yl la nt hu s a m ar us Ph yl la nt ha ce ae Bl oc ke d th e in te ra ct io n of H IV -1 gp 12 0 w ith C D 4 In hi bi tio n of v iru s en tr y in hi bi te d ke y en zy m es R T, IN a nd P R In hi bi tio n of H IV -1 re pl ic at io n af te r o ra l a pp lic at io n H er ba l e xt ra ct In v itr o & ex v iv o 1 m g/ m l i n vi tro 12 00 m g; s in gl e do se in h um an M T4 c el ls H IV -1 10 6 Tr ic hi lia g la br a M el ia ce ae Re du ct io n in V SV ti te r Le af m et ha no lic e xt ra ct In v itr o 0. 25 m g/ m l Ve ro c el ls Ve si cu la r st om at iti s vi ru s (V SV ) a nd H SV -1 14 1 G ly ci ne m ax Fa ba ce ae In hi bi t v iru s re pl ic at io n H er ba l e xt ra ct In v itr o 0. 1- 5 m g/ m l H eL a ce lls FL c el ls M D CK c el ls Ve ro c el ls H um an ad en ov iru s ty pe 1, c ox sa ck ie B 1 an d in flu en za A 10 7 A za di ra ch ta in di ca M el ia ce ae In hi bi t v iru s re pl ic at io n in hi bi tio n of v ira l R N A re pl ic at io n Le af e xt ra ct In v itr o & in v iv o 1. 89 7 m g/ m l 12 0– 30 m g/ m l C6 /3 6 ce ll lin e M ic e D en gu e vi ru s ty pe -2 (D EN -2 ) 10 7 Eu ca ly pt us c am al du le ns is M yr ta ce ae Vi ru ci da l a ct iv ity Es se nt ia l o il Le av es e xt ra ct In v itr o 0. 85 ± 0. 15 μ g/ m l 0. 1± 0. 00 8 μg /m l 0. 3± 0. 00 2 μg /m l H ep -2 M A 10 4 BG M Ve ro H SV , v ar ic el la zo st er , p ol io vi ru s, ec ho vi ru s, Co xs ac ki e B4 , ro ta vi ru s 12 4- 12 6 A rt em is ia p ri nc ep s As te ra ce ae Pl aq ue fo rm at io n in hi bi to r Es se nt ia l o il In v itr o 0. 1% (v /v ) ( es se nt ia l oi l) RA W 2 64 .7 CR FK Ca lic iv iru s- F9 a nd M N V- 1 12 7, 1 28 M os la d ia nt he ra La m ia ce ae Re pl ic at io n in hi bi to r d ec re as e of c yt ok in e pr od uc tio ns (I FN -γ an d IL -4 ) e nh an ci ng a nt io xi da nt ac tiv iti es Es se nt ia l o il In v iv o 90 –3 60 m g/ kg IC R m ic e In flu en za A 12 1 H et er ot ha la m us a lie nu s, Bu dd le ja c or do be ns is As te ra ce ae & Sc ro ph ul ar ia ce ae Vi ru ci da l a ct iv ity Es se nt ia l o il In v itr o CC 50 (p pm ): 14 7. 6 ± 5. 7 an d 15 7. 2 ± 3. 5 Ve ro H SV -1 , D EN V- 2, an d JU N V 12 9 Co ri do th ym us c ap it at us , O ri ga nu m d ic ta m nu s, S al vi a fr ut ic os a La m ia ce ae Re pl ic at io n cy cl e an d pr og en y vi ru s pr od uc tio n M ix es e ss en tia l o il In v itr o 15 m L/ L H eL a M D CK H 1N 1 in flu en za vi ru s an d H RV 14 rh in ov iru s 12 2 M el al eu ca a lte rn ifo lia M yr ta ce ae Vi ru ci da l a ct iv ity Es se nt ia l o il In v itr o 0. 00 06 % (v ⁄ v ) M D CK In flu en za A su bt yp e H 1N 1 12 3 La ur us n ob ili s La ur ac ea e IC 50 Re pl ic at io n in hi bi to ry Es se nt ia l o il (β -o ci m en e, 1, 8- ci ne ol e, α -p in en e, an d β- pi ne ne ) In v itr o 12 0 m g/ m l Ve ro Co ro na vi ru s SA RS 12 0 Li pp ia ju ne lli an a, L ip pi a tu rb in at e Ve rb en ac ea e & As te ra ce ae Vi ru ci da l a ct iv ity Es se nt ia l o il In v itr o VC 50 = 1 4– 20 p pm Ve ro JU N V 13 0 Eu pa to ri um p at en s As te ra ce ae Vi ru ci da l a ct iv ity Es se nt ia l o il In v itr o VC 50 = 1 50 p pm Ve ro D en gu e vi ru s ty pe 2 (D EN -2 ) 13 0 Ci nn am om um z ey la ni cu m , D au cu sc ar ot a, E uc al yp tu s gl ob ul us , R os m ar in us offi ci na lis La ur ac ea e, A pi ac ea e, M yr ta ce ae , La m ia ce ae Re du ce d vi ra l u ni ts v iri on en ve lo pe s tr uc tu re s Es se nt ia l o il bl en d In v itr o - Ve ro H 1N 1 su bt yp e of in flu en za A v iru s 13 1- 13 3 Fo rt un el la m ar ga ri ta Ru ta ce ae Vi ru ci da l a ct iv ity Fr ui ts a nd le av es es se nt ia l o il (α -t er pi ne ol ) In v itr o 6. 77 µg /m L (fr ui ts ) 38 .8 9 µg /m L (le av es ) M D CK In flu en za v iru s su bt yp e H 5N 1 13 4 M el is sa o ffi ci na lis La m ia ce ae Vi ru ci da l a ct iv ity Re pl ic at io n in hi bi to ry Es se nt ia l o il In v itr o 0. 5- 0. 1 m g/ m l M D CK Av ia n in flu en za H 9N 2 su bt yp e 13 5 Po go st em on c ab lin La m ia ce ae Vi ru ci da l a ct iv ity im pr ov in g th e im m un e re sp on se a tt en ua tin g sy st em ic in fla m m at or y re sp on se s Es se nt ia l o il In v iv o 10 -8 0 m g/ kg M ic e H 1N 1 & H 2N 2 in flu en za v iru s 13 6- 13 8 Tr ac hy sp er m um a m m i A pi ac ea e Re du ct io n vi ru s tit er Vi ru ci da l a ct iv ity Es se nt ia l o il In v itr o 0. 5m g/ m l Ve ro Ja pa ne se en ce ph al iti s vi ru s 13 9 A lo e ve ra (L .) As ph od el ac ea e 3C Lp ro in hi bi to ry H er ba l e xt ra ct In v itr o 42 8 μg /m L - SA RS Co v- 2 11 6 https://en.wikipedia.org/wiki/Moraceae https://en.wikipedia.org/wiki/Asteraceae https://en.wikipedia.org/wiki/Asteraceae https://en.wikipedia.org/wiki/Adoxaceae https://en.wikipedia.org/wiki/Sapindaceae https://en.wikipedia.org/wiki/Urticaceae https://www.google.com/search?sxsrf=ALeKk019ROO1Ju0h1I1zncfDTk7D58A5hg:1587287356728&q=Polygonaceae&stick=H4sIAAAAAAAAAONgVuLQz9U3MC3JzVjEyhOQn1OZnp-XmJyamAoAAoTq0BsAAAA&sa=X&ved=2ahUKEwi2lbeYkvToAhVFKuwKHb0QC3YQmxMoATAdegQIDhAD&sxsrf=ALeKk019ROO1Ju0h1I1zncfDTk7D58A5hg:1587287356728 https://www.google.com/search?sxsrf=ALeKk01fdYNwJHXP35coe5F2vZsl5W5_tA:1587287454997&q=Malvaceae&stick=H4sIAAAAAAAAAONgVuLUz9U3MMwuzClexMrpm5hTlpicmpgKADzZVnIZAAAA&sa=X&ved=2ahUKEwi8-qTHkvToAhWEDuwKHQXBAdEQmxMoATAVegQIDhAD&sxsrf=ALeKk01fdYNwJHXP35coe5F2vZsl5W5_tA:1587287454997 https://www.google.com/search?biw=1455&bih=717&sxsrf=ALeKk00BYhXkwokF_AZrR02pbv38cwoeRA:1587287489917&q=Phyllanthaceae&stick=H4sIAAAAAAAAAONgVuLUz9U3MM0xzjZaxMoXkFGZk5OYV5KRmJyamAoArAPBwR4AAAA&sa=X&ved=2ahUKEwiVrvjXkvToAhXQzaQKHeZ2ARAQmxMoATAdegQIDhAD https://en.wikipedia.org/wiki/Fabaceae https://www.google.com/search?sxsrf=ALeKk02oKdEl39YYni4B_97umweUJd0k2w:1587287568262&q=Meliaceae&stick=H4sIAAAAAAAAAONgVuLQz9U3SLZMylnEyumbmpOZmJyamAoA4_jqMBgAAAA&sa=X&ved=2ahUKEwjXnKb9kvToAhWPM-wKHeuJCI4QmxMoATAhegQIDRAD&sxsrf=ALeKk02oKdEl39YYni4B_97umweUJd0k2w:1587287568262 https://en.wikipedia.org/wiki/Myrtaceae https://en.wikipedia.org/wiki/Asteraceae https://en.wikipedia.org/wiki/Asteraceae https://en.wikipedia.org/wiki/Scrophulariaceae https://en.wikipedia.org/wiki/Lamiaceae https://en.wikipedia.org/wiki/Myrtaceae https://en.wikipedia.org/wiki/Lauraceae https://en.wikipedia.org/wiki/Asteraceae https://en.wikipedia.org/wiki/Asteraceae https://www.google.com/search?sxsrf=ALeKk00PWPSa5caipyv80-SOo-nhipYAeA:1587284962097&q=Lauraceae&stick=H4sIAAAAAAAAAONgVuLUz9U3MMxOL7FcxMrpk1halJicmpgKAB7IW7gZAAAA&sa=X&ved=2ahUKEwiIzcqiifToAhWVh1wKHWW5Cg8QmxMoATAeegQIDxAD&sxsrf=ALeKk00PWPSa5caipyv80-SOo-nhipYAeA:1587284962097 https://en.wikipedia.org/wiki/Apiaceae https://en.wikipedia.org/wiki/Myrtaceae https://www.google.com/search?sxsrf=ALeKk01Q-CejpPx7Rnwm3iooSWqYVgtfeg:1587285072773&q=Lamiaceae&stick=H4sIAAAAAAAAAONgVuLQz9U3MMnKMV_EyumTmJuZmJyamAoA5oowihgAAAA&sa=X&ved=2ahUKEwjpza3XifToAhXC6aQKHXr5D10QmxMoATAeegQIDRAD&sxsrf=ALeKk01Q-CejpPx7Rnwm3iooSWqYVgtfeg:1587285072773 https://www.google.com/search?sxsrf=ALeKk03P5R-oH8IBbyZ-uWhnxGPa6p7dzg:1587285112214&q=Rutaceae&stick=H4sIAAAAAAAAAONgVuLQz9U3yC4oMHrE6Mgt8PLHPWEpi0lrTl5jNOLiCs7IL3fNK8ksqRRS4WKDsqS4eKTgmjQYpLi44DyeRawcQaUlicmpiakAdUnxuVsAAAA&sxsrf=ALeKk03P5R-oH8IBbyZ-uWhnxGPa6p7dzg:1587285112214 https://en.wikipedia.org/wiki/Lamiaceae https://en.wikipedia.org/wiki/Lamiaceae https://en.wikipedia.org/wiki/Apiaceae https://www.google.com/search?rlz=1C1GCEA_enIR901IR901&sxsrf=ALeKk00lQ8iD-hai0WATxNCeuJeDfn6Qdw:1591690208373&q=Asphodelaceae&stick=H4sIAAAAAAAAAONgVuLUz9U3MCovT6pYxMrrWFyQkZ-SmpOYnJqYCgCDPohhHQAAAA&sa=X&ved=2ahUKEwiondmLpPTpAhXTZxUIHdKzCKsQmxMoATApegQIBxAD 13 Review A narrative review of herbal preparations against RNA virusesSaeideh Momtaz et al. J Contemp Med Sci | Vol. 7, No. 1, January-February 2021: 6 – 22 Ta bl e 3. M ed ic in al p la nt s i nv es tig at ed a ga in st co ro na vi ru se s a nd re la te d vi ru se s. Sc ie nt ifi c n am e  Fa m ily M ec ha ni sm He rb al p ro du ct Ty pe o f st ud y Eff ec tiv e do sa ge Ce ll ty pe /a ni m al m od el Vi ru s Re fe re nc e M or us sp p. M or ac ea e In hi bi tio n of v ira l i nf ec tiv ity Le av es a nd s te m b ar k ex tr ac t In v itr o 5 µg /m L L- 13 2 co ro na vi ru s (H Co V 22 9E ) (1 02 ) Ec hi na ce a pu rp ur ea As te ra ce ae Vi ru ci da l a ct iv ity H er ba l e xt ra ct In v itr o 3. 2 µg /m l H uh -7 Ve ro A 9 M ER S- a nd S A RS - Co Vs 10 3 A nt he m is h ya lin a As te ra ce ae D ec re as e vi ru s lo ad a nd IL -8 de cr ea se T RP g en es e xp re ss io n Et ha no lic e xt ra ct In v itr o - H eL a ce ac am i Co ro na vi ru s M H V- A 59 10 5 Sa m bu cu s n ig ra Ad ox ac ea e Im pr ov e sy m pt om s an d ov er al l w el lb ei ng H er ba l e xt ra ct A C lin ic al tr ia l 15 m l o f s yr up fo ur tim es a d ay , f or 5  d ay s - In flu en za 10 8 U va ri a an go le ns is A nn on ac ea e H IV -1 R N as e H e nz ym e an d re ve rs e tr an sc rip ta se a ct iv ity M et ha no l s te m b ar k ex tr ac t In v itr o 1. 0  ±  0 .2 a nd 0. 62  ±  0 .1 5  μg /m L A 54 9 H IV -1 10 4 Po m et ia p in na ta Sa pi nd ac ea e Ac tiv ity a ga in st H IV -1 in te gr as e Et ha no l l ea ve s ex tr ac t In v itr o 8. 8 µg /m L - H IV -1 95 Bo eh m er ia n iv ea U rt ic ac ea e In hi bi t H BV D N A s ec re tio n in to su pe rn at an t Ro ot e xt ra ct In v itr o 10 m g/ L H ep G 2 2. 2. 15 hu m an he pa to bl as to m a H BV 11 0 Po ly go nu m c us pi da tu m Po ly go na ce ae In cr ea se e xp re ss io n of H Bs Ag de cr ea se H BV D N A in th e su sp en si on Et ha no lic e xt ra ct In v itr o 30 μ g/ m l H ep G 2 2. 2. 15 hu m an he pa to bl as to m a H BV 11 1 G ua zu m a ul m ifo lia M al va ce ae In hi bi te d re pl ic at io n bl oc k th e sy nt he si s of vi ra la nt ig en s H er ba l e xt ra ct In v itr o 5 m g/ m l H Ep -2 (h um an la ry nx c ar ci no m a) ce lls Po lio vi ru s- 1 & Bo vi ne H er pe sv iru s 11 2 O le a eu ro pa ea O le ac ea e D ec re as e VH SV ti te rs a nd v ira l pr ot ei n ac cu m ul at io n in hi bi ts re pl ic at io n m od ul at e ho st c el l g en e ex pr es si on p ro fil e Le af e xt ra ct In v itr o 0. 6– 1 m g/ m l Ep ith el io m a pa pu lo su m cy pr in id M T2 c el l l in e H em or rh ag ic se pt ic ae m ia v iru s (V H SV ) a nd H IV -1 11 4, 1 40 Ph yl la nt hu s a m ar us Ph yl la nt ha ce ae Bl oc ke d th e in te ra ct io n of H IV -1 gp 12 0 w ith C D 4 In hi bi tio n of v iru s en tr y in hi bi te d ke y en zy m es R T, IN a nd P R In hi bi tio n of H IV -1 re pl ic at io n af te r o ra l a pp lic at io n H er ba l e xt ra ct In v itr o & ex v iv o 1 m g/ m l i n vi tro 12 00 m g; s in gl e do se in h um an M T4 c el ls H IV -1 10 6 Tr ic hi lia g la br a M el ia ce ae Re du ct io n in V SV ti te r Le af m et ha no lic e xt ra ct In v itr o 0. 25 m g/ m l Ve ro c el ls Ve si cu la r st om at iti s vi ru s (V SV ) a nd H SV -1 14 1 G ly ci ne m ax Fa ba ce ae In hi bi t v iru s re pl ic at io n H er ba l e xt ra ct In v itr o 0. 1- 5 m g/ m l H eL a ce lls FL c el ls M D CK c el ls Ve ro c el ls H um an ad en ov iru s ty pe 1, c ox sa ck ie B 1 an d in flu en za A 10 7 A za di ra ch ta in di ca M el ia ce ae In hi bi t v iru s re pl ic at io n in hi bi tio n of v ira l R N A re pl ic at io n Le af e xt ra ct In v itr o & in v iv o 1. 89 7 m g/ m l 12 0– 30 m g/ m l C6 /3 6 ce ll lin e M ic e D en gu e vi ru s ty pe -2 (D EN -2 ) 10 7 Eu ca ly pt us c am al du le ns is M yr ta ce ae Vi ru ci da l a ct iv ity Es se nt ia l o il Le av es e xt ra ct In v itr o 0. 85 ± 0. 15 μ g/ m l 0. 1± 0. 00 8 μg /m l 0. 3± 0. 00 2 μg /m l H ep -2 M A 10 4 BG M Ve ro H SV , v ar ic el la zo st er , p ol io vi ru s, ec ho vi ru s, Co xs ac ki e B4 , ro ta vi ru s 12 4- 12 6 A rt em is ia p ri nc ep s As te ra ce ae Pl aq ue fo rm at io n in hi bi to r Es se nt ia l o il In v itr o 0. 1% (v /v ) ( es se nt ia l oi l) RA W 2 64 .7 CR FK Ca lic iv iru s- F9 a nd M N V- 1 12 7, 1 28 M os la d ia nt he ra La m ia ce ae Re pl ic at io n in hi bi to r d ec re as e of c yt ok in e pr od uc tio ns (I FN -γ an d IL -4 ) e nh an ci ng a nt io xi da nt ac tiv iti es Es se nt ia l o il In v iv o 90 –3 60 m g/ kg IC R m ic e In flu en za A 12 1 H et er ot ha la m us a lie nu s, Bu dd le ja c or do be ns is As te ra ce ae & Sc ro ph ul ar ia ce ae Vi ru ci da l a ct iv ity Es se nt ia l o il In v itr o CC 50 (p pm ): 14 7. 6 ± 5. 7 an d 15 7. 2 ± 3. 5 Ve ro H SV -1 , D EN V- 2, an d JU N V 12 9 Co ri do th ym us c ap it at us , O ri ga nu m d ic ta m nu s, S al vi a fr ut ic os a La m ia ce ae Re pl ic at io n cy cl e an d pr og en y vi ru s pr od uc tio n M ix es e ss en tia l o il In v itr o 15 m L/ L H eL a M D CK H 1N 1 in flu en za vi ru s an d H RV 14 rh in ov iru s 12 2 M el al eu ca a lte rn ifo lia M yr ta ce ae Vi ru ci da l a ct iv ity Es se nt ia l o il In v itr o 0. 00 06 % (v ⁄ v ) M D CK In flu en za A su bt yp e H 1N 1 12 3 La ur us n ob ili s La ur ac ea e IC 50 Re pl ic at io n in hi bi to ry Es se nt ia l o il (β -o ci m en e, 1, 8- ci ne ol e, α -p in en e, an d β- pi ne ne ) In v itr o 12 0 m g/ m l Ve ro Co ro na vi ru s SA RS 12 0 Li pp ia ju ne lli an a, L ip pi a tu rb in at e Ve rb en ac ea e & As te ra ce ae Vi ru ci da l a ct iv ity Es se nt ia l o il In v itr o VC 50 = 1 4– 20 p pm Ve ro JU N V 13 0 Eu pa to ri um p at en s As te ra ce ae Vi ru ci da l a ct iv ity Es se nt ia l o il In v itr o VC 50 = 1 50 p pm Ve ro D en gu e vi ru s ty pe 2 (D EN -2 ) 13 0 Ci nn am om um z ey la ni cu m , D au cu sc ar ot a, E uc al yp tu s gl ob ul us , R os m ar in us offi ci na lis La ur ac ea e, A pi ac ea e, M yr ta ce ae , La m ia ce ae Re du ce d vi ra l u ni ts v iri on en ve lo pe s tr uc tu re s Es se nt ia l o il bl en d In v itr o - Ve ro H 1N 1 su bt yp e of in flu en za A v iru s 13 1- 13 3 Fo rt un el la m ar ga ri ta Ru ta ce ae Vi ru ci da l a ct iv ity Fr ui ts a nd le av es es se nt ia l o il (α -t er pi ne ol ) In v itr o 6. 77 µg /m L (fr ui ts ) 38 .8 9 µg /m L (le av es ) M D CK In flu en za v iru s su bt yp e H 5N 1 13 4 M el is sa o ffi ci na lis La m ia ce ae Vi ru ci da l a ct iv ity Re pl ic at io n in hi bi to ry Es se nt ia l o il In v itr o 0. 5- 0. 1 m g/ m l M D CK Av ia n in flu en za H 9N 2 su bt yp e 13 5 Po go st em on c ab lin La m ia ce ae Vi ru ci da l a ct iv ity im pr ov in g th e im m un e re sp on se a tt en ua tin g sy st em ic in fla m m at or y re sp on se s Es se nt ia l o il In v iv o 10 -8 0 m g/ kg M ic e H 1N 1 & H 2N 2 in flu en za v iru s 13 6- 13 8 Tr ac hy sp er m um a m m i A pi ac ea e Re du ct io n vi ru s tit er Vi ru ci da l a ct iv ity Es se nt ia l o il In v itr o 0. 5m g/ m l Ve ro Ja pa ne se en ce ph al iti s vi ru s 13 9 A lo e ve ra (L .) As ph od el ac ea e 3C Lp ro in hi bi to ry H er ba l e xt ra ct In v itr o 42 8 μg /m L - SA RS Co v- 2 11 6 https://en.wikipedia.org/wiki/Moraceae https://en.wikipedia.org/wiki/Asteraceae https://en.wikipedia.org/wiki/Asteraceae https://en.wikipedia.org/wiki/Adoxaceae https://en.wikipedia.org/wiki/Sapindaceae https://en.wikipedia.org/wiki/Urticaceae https://www.google.com/search?sxsrf=ALeKk019ROO1Ju0h1I1zncfDTk7D58A5hg:1587287356728&q=Polygonaceae&stick=H4sIAAAAAAAAAONgVuLQz9U3MC3JzVjEyhOQn1OZnp-XmJyamAoAAoTq0BsAAAA&sa=X&ved=2ahUKEwi2lbeYkvToAhVFKuwKHb0QC3YQmxMoATAdegQIDhAD&sxsrf=ALeKk019ROO1Ju0h1I1zncfDTk7D58A5hg:1587287356728 https://www.google.com/search?sxsrf=ALeKk01fdYNwJHXP35coe5F2vZsl5W5_tA:1587287454997&q=Malvaceae&stick=H4sIAAAAAAAAAONgVuLUz9U3MMwuzClexMrpm5hTlpicmpgKADzZVnIZAAAA&sa=X&ved=2ahUKEwi8-qTHkvToAhWEDuwKHQXBAdEQmxMoATAVegQIDhAD&sxsrf=ALeKk01fdYNwJHXP35coe5F2vZsl5W5_tA:1587287454997 https://www.google.com/search?biw=1455&bih=717&sxsrf=ALeKk00BYhXkwokF_AZrR02pbv38cwoeRA:1587287489917&q=Phyllanthaceae&stick=H4sIAAAAAAAAAONgVuLUz9U3MM0xzjZaxMoXkFGZk5OYV5KRmJyamAoArAPBwR4AAAA&sa=X&ved=2ahUKEwiVrvjXkvToAhXQzaQKHeZ2ARAQmxMoATAdegQIDhAD https://en.wikipedia.org/wiki/Fabaceae https://www.google.com/search?sxsrf=ALeKk02oKdEl39YYni4B_97umweUJd0k2w:1587287568262&q=Meliaceae&stick=H4sIAAAAAAAAAONgVuLQz9U3SLZMylnEyumbmpOZmJyamAoA4_jqMBgAAAA&sa=X&ved=2ahUKEwjXnKb9kvToAhWPM-wKHeuJCI4QmxMoATAhegQIDRAD&sxsrf=ALeKk02oKdEl39YYni4B_97umweUJd0k2w:1587287568262 https://en.wikipedia.org/wiki/Myrtaceae https://en.wikipedia.org/wiki/Asteraceae https://en.wikipedia.org/wiki/Asteraceae https://en.wikipedia.org/wiki/Scrophulariaceae https://en.wikipedia.org/wiki/Lamiaceae https://en.wikipedia.org/wiki/Myrtaceae https://en.wikipedia.org/wiki/Lauraceae https://en.wikipedia.org/wiki/Asteraceae https://en.wikipedia.org/wiki/Asteraceae https://www.google.com/search?sxsrf=ALeKk00PWPSa5caipyv80-SOo-nhipYAeA:1587284962097&q=Lauraceae&stick=H4sIAAAAAAAAAONgVuLUz9U3MMxOL7FcxMrpk1halJicmpgKAB7IW7gZAAAA&sa=X&ved=2ahUKEwiIzcqiifToAhWVh1wKHWW5Cg8QmxMoATAeegQIDxAD&sxsrf=ALeKk00PWPSa5caipyv80-SOo-nhipYAeA:1587284962097 https://en.wikipedia.org/wiki/Apiaceae https://en.wikipedia.org/wiki/Myrtaceae https://www.google.com/search?sxsrf=ALeKk01Q-CejpPx7Rnwm3iooSWqYVgtfeg:1587285072773&q=Lamiaceae&stick=H4sIAAAAAAAAAONgVuLQz9U3MMnKMV_EyumTmJuZmJyamAoA5oowihgAAAA&sa=X&ved=2ahUKEwjpza3XifToAhXC6aQKHXr5D10QmxMoATAeegQIDRAD&sxsrf=ALeKk01Q-CejpPx7Rnwm3iooSWqYVgtfeg:1587285072773 https://www.google.com/search?sxsrf=ALeKk03P5R-oH8IBbyZ-uWhnxGPa6p7dzg:1587285112214&q=Rutaceae&stick=H4sIAAAAAAAAAONgVuLQz9U3yC4oMHrE6Mgt8PLHPWEpi0lrTl5jNOLiCs7IL3fNK8ksqRRS4WKDsqS4eKTgmjQYpLi44DyeRawcQaUlicmpiakAdUnxuVsAAAA&sxsrf=ALeKk03P5R-oH8IBbyZ-uWhnxGPa6p7dzg:1587285112214 https://en.wikipedia.org/wiki/Lamiaceae https://en.wikipedia.org/wiki/Lamiaceae https://en.wikipedia.org/wiki/Apiaceae https://www.google.com/search?rlz=1C1GCEA_enIR901IR901&sxsrf=ALeKk00lQ8iD-hai0WATxNCeuJeDfn6Qdw:1591690208373&q=Asphodelaceae&stick=H4sIAAAAAAAAAONgVuLUz9U3MCovT6pYxMrrWFyQkZ-SmpOYnJqYCgCDPohhHQAAAA&sa=X&ved=2ahUKEwiondmLpPTpAhXTZxUIHdKzCKsQmxMoATApegQIBxAD 14 Review A narrative review of herbal preparations against RNA viruses Saeideh Momtaz et al. J Contemp Med Sci | Vol. 7, No. 1, January-February 2021: 6 – 22 antimicrobial. G. ulmifoli extract inhibited poliovirus-1 rep- lication by 26% in HEP-2 cells and restricted the synthesis of viral antigens in the infected cell culture.112 Azadirachta indica Azadirachta indica (Neem) is grown in tropical countries and has been reported to possess anti-inflammatory, antipyretic, and hypoglycemic activities. The aqueous extract of the leaves of A. indica inhibited Dengue virus type-2 (DEN-2) in vitro C6/36 cell line and in vivo (mice).113 Olea europaea Olive leaf extract inhibited replication of viral hemorrhagic septicaemia virus (VHSV).114 The extract also inhibited acute infection and cell-to-cell transfer of HIV-1 virus in MT2 cell line.115 Aloe vera A set of experiments suggested that A. vera has potent anti- viral activity. A. vera contains bioactive virucidal compounds such as anthraquinones. As mentioned, anthraquinones like some antiviral drugs (Lopinavir, ritonavir), alone or in com- bination with other medications, can target SARSCov-2 pro- tease 3CLPro.116 Acemannan is the predominant acetylated polysaccharide mannan extracted from A. vera gel and has been approved by the US FDA for the treatment of HIV-1 in humans. Acemannan inhibits glycosylation of viral proteins and inhibits cell fusion and suppression of virus release.117 Essential oils Essential oils contain a large number of compounds and may target several purposes. However, in most cases, synergis- tic mechanisms are involved in their antimicrobial activity. Studies have shown essential oils are complex mixtures of lipophilic and volatile secondary metabolites isolated from plants such as monoterpenes (hydrocarbon and oxygenated monoterpens), sesquiterpenes (hydrocarbon and oxygenated sesquiterpens), and/or phenylpropanoids that are responsible for a broad biological functions such as antimicrobial, antiox- idant, anti-inflammatory, anticancer, cancer chemoprotective, repellent and insecticidal, allelopathic, cytotoxicity, and anti- viral activities.118, 119 Laurus nobilis The essential of the leaves of L. nobilis has been shown to have potent antiviral activity against coronavirus SARS. The most important compounds in the essence of this herb include β-ocimene, 1,8-cineole, α-pinene, and β-pinene. The IC50 of L. nobilis was measured 120 mg/ml with a selective index of 4.2 (SI; TC50/IC50).120 Mosla dianthera This herb is used as an aromatic herb in traditional medi- cine in the treatment of cough, colds, fever, bronchitis, nasal hyperemia, and headache. The effect of the essential oil of this herb on mice infected by influenza A was investigated. It was found that this essence has significant effects, includ- ing reducing viral lung titers, inhibiting pneumonia, lowering serum levels of IFN-γ and interleukin 4 (IL-4), and enhancing the antioxidant activity in lung tissue of mice infected with influenza A.121 Coridothymus capitatus, Origanum dictamnus and Salvia fruticosa A mixture of aromatic plant essential oils consisted of C. cap- itatus, O. dictamnus, and S. fruticosa was tested against the H1N1 influenza virus and HRV14 rhinovirus in HeLa and MDCK cells. It was found that this compound caused a defect in the nucleoprotein trafficking of the virus in vitro, thereby, has the potential to be used as an herbal drug against respi- ratory system viruses such as H1N1 influenza and rhinovirus HRV14.122 Melaleuca alternifolia The antiviral effect of this essence on the MDCK cell line was investigated using plaque reduction assay. The results of this study confirmed the antiviral activity of the essence of M. alternifolia against influenza A subtype H1N1, which was implicated to the presence of terpinen-4-ol, as the essence active ingredient.123 Eucalyptus camaldulensis The essential oil of E. camaldulensis reduced the proliferation of Coxsackie B4, rotavirus, and herpes simplex virus (HSV). Moreover, the methanolic extract of this plant attenuated the activity of HSV, varicella zoster, poliovirus, and echovirus.124-126 Artemisia princeps The essential oil of A. princeps var. orientalis and its bioactive components, including Borneol, Athujone, and Camphor, were studied on two noroviruses; MNV-1 and calicivirus-F9 by time-of-addition plaque assays. The A. princeps essence at concentrations of 0.1 and 0.01 inhibited the growth of cali- civirus-F9 and MNV-1 by 48% and 64% (v/v), respectively. Borneol and Camphor showed no antiviral activity, whereas Athujone, the major compound of the essence, strongly and dose-dependently inhibited virus infection.127, 128 Heterothalamus alienus and Buddleja cordobensis In a study on seven herbs (Pectis odorata, Gaillardia mega- potamica, Heterothalamus alienus, Aloysia triphylla, Artemisia mendozana, Jungia polita, Buddleja cordobensis) indigenous to the South America, their cellular properties (cytotoxicity) and their inhibitory effects on HSV-1, Dengue Virus Type 2 (DENV-2) (causing Dengue fever, Dengue hemorrhagic fever, and Dengue shock syndrome), and Junin virus (JUNV) (the cause of Argentine hemorrhagic fever) were evaluated. The strongest association between cytotoxicity and antiviral activ- ities was observed for the essence of Hetero-thalamus alienus and B. cordobensis against JUNV virus.129 Lippia junelliana and Lippia turbinate The essential oils of South American species named as L. junelliana and L. turbinate could temperature- and time- dependently inhibit JUNV in Vero cells in vitro (VC50: 14–20 ppm).130 Eupatorium patens The essential oil of the leaves, flowers, and fruits of E. pat- ens (Asteraceae), indigenous to South America, potently restrained the DEN-2 replication (VC50: 150 ppm). The https://www.sciencedirect.com/topics/medicine-and-dentistry/dengue-fever https://www.sciencedirect.com/topics/medicine-and-dentistry/dengue-fever 15 Review A narrative review of herbal preparations against RNA virusesSaeideh Momtaz et al. J Contemp Med Sci | Vol. 7, No. 1, January-February 2021: 6 – 22 main components of the essential oil were D-germacrene; β-caryophyllene; bicyclogermacrene; α-pinene; caryophyllene oxide.130 Cinnamomum zeylanicum, Daucuscarota, Eucalyptus globulus and Rosmarinus officinalis The blend of essential oil of these herbs inhibited H1N1 sub- type of influenza A virus function, probably through inter- fering the formation of the virus coat and inhibiting its DNA polymerase enzyme. For H1N1, a reduction was greater than 99%.131-133 Fortunella margarita The essential oil compound of the fruit and leaves of F. mar- garita was found effective against avian influenza virus sub- type H5N1 in MDCK cell line, which was associated with the presence of α-terpineol in its fruit. The fruit essential oil has been shown to be more effective and caused an 80% inhibition of the virus activity.134 Melissa officinalis The inhibitory effect of the essential oil of M. officinalis on the avian influenza H9N2 subtype was investigated in the MDCK cell line. It has been found that this herb has a synergistic effect in inhibiting the H9N2 virus with Noseltamivir. M. officina- lis can interact with cell surface proteins (i.e., masking the cell surface), thereby blocking the virus binding to cellular receptors.135 Pogostemon cablin The antiviral activity of the essential oil obtained from P. cablin has been demonstrated against H1N1 and H2N2 influenza virus. Oral administration of P. cablin essential oil in mice has also been shown to protect against influenza virus infection by enhancing the immune response and decreasing the systemic and pulmonary inflammatory response.136-138 Trachyspermum ammi The essential oil of T. mumammi was found efficient against the Japanese encephalitis virus (JEV) in vitro. JEV titration was determined by plaque assay, and the antiviral activity of this plant was measured in vitro using a plaque reduction neu- tralization test. Treatment of Vero cell line with this essential oil in both pre- and post-exposure treatments reduced the virus titers by 80% and 40%, respectively.139 Herbal active biochemicals Cinnamaldehyde Cinnamaldehyde, an abundant aromatic phenylpropanoid in Cinnamomi cortex (Cinnamomum verum) has been studied for its potential properties against the influenza virus. The results of reverse transcription (RT-PCR) and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) anal- yses showed that cinnamaldehyde inhibited the synthesis of influenza virus proteins at the post-transcriptional level. In mice infected with influenza virus, inhalation (50 mg in the cage daily) and nasal inoculation (250 g for each rat daily) of this compound over 8 days increased the survival rate from 20% to 100% and 70%, respectively. Importantly, inhalation of cinnamaldehyde reduced virus titers in the bronchoalveolar lavage on the sixth day after infection142 (Table 4). 5,7,3’, 4’-tetrahydroxy-2’ - (3,3-dimethylallyl) isoflavone 5,7,3’, 4’-tetrahydroxy-2’ - (3,3-dimethylallyl) isoflavone, is extracted from Psorothamnus arborescens. The anti- leishmanial property of this compound has already been proven in the scientific literature. Chymotrypsin virus-like cysteine protease enzyme (3CLpro) is an essential factor for the replication cycle of coronavirus, representing a potential target for the treatment of such disease. This compound has a high affinity to the catalytic domain of 3CLpro enzyme. It also can bind receptor-binding residues of the 3CLpro143, 144 (Table 4). 1,2,3,4,6-penta-O-galloyl-β-D-glucoside A compound called 1,2,3,4,6-penta-O-galloyl-β-D-glucoside, extractable from the aerial parts of Saxifraga melanocentra, is responsible for the anti-hepatitis C virus (HCV) effect of the herb. The compound was also a potent inhibitor of the HCV serine protease enzyme145 (Table 4). Myricitrin and Scutellarin Myricitrin can be obtained from a plant called Myrica cerifera. It also can bind to and inhibit the catalytic domain of 3CLpro enzyme with high affinity. Modeling analysis also showed that Scutellarin or Myristine from Scutellaria baicalensis could directly link the ATP/ADP binding site of the SARS-CoV virus helicase enzyme (nsP13), thereby preventing direct binding of ATP/ADP to it. In particular, Myricetin interferes with the ATPase activity of the SARS-CoV protein helicase. It is likely to do so by directly interacting with essential residues of the ATPase domain, such as N265, Y269, and R443146, 147 (Table 4). Glycyrrhizin and Licorine Glycyrrhizin, the bioactive component of Licorice and Lycorine from red spider lily (Lycoris radiata), exhibited a potent anti-SARS-CoV Corona activity. However, the effec- tive concentration of Glycyrrhizin (EC50) for inhibiting viral infection was very high (EC50 300 mg/L). Glycyrrhizin was most effective when given both during and after the adsorp- tion period148, 149 (Table 4). Quercetin Quercetin is the most abundant dietary plant pigment flavo- noid (i.e., in onion and garlic). It was reported that this com- pound inhibited the activity of 3CLPro of SARS-CoV with a FRET method. Its shown quercetin has low toxicity to the cells in vitro. Their MERS‐CoV 3CLpro inhibitory activity is lower than their corresponding compounds at 40 μM150 (Table 4). Baicalein Scutellaria baicalensis is one of the genus that may use as a source of this flavonoid. Ethanolic extract of S. baicalensis inhibited SARS-CoV-2 3CLpro activity in vitro and the replica- tion of SARS-CoV-2 in Vero cells with an EC50 of 0.74 µg/ml. Baicalein strongly inhibited SARS-CoV-2 3CLpro activity with an IC50 of 0.39 µM151 (Table 4). 16 Review A narrative review of herbal preparations against RNA viruses Saeideh Momtaz et al. J Contemp Med Sci | Vol. 7, No. 1, January-February 2021: 6 – 22 Ta bl e 4. A nt iv ira l p hy to ch em ic al s e ffe ct iv e on R NA v iru se s. Co m po un d So ur ce He rb al fa m ily Vi ru ci da l t ar ge t Ty pe o f st ud y Eff ec tiv e do sa ge Ce ll ty pe /a ni m al m od el Vi ru s Re fe re nc e M yr ic it ri n M yr ic a ce rif er a M yr ic ac ea e 3C Lp ro in hi bi to ry (a n ec es sa ry pr ot ea se fo r v ira l g ro w th ) 3D st ru ct ur e si m ul at io n - - SA RS -C oV -2 14 6 Sc ut el la ri n Sc ut el la ria b ai ca le ns is La m ia ce ae H el ic as e (n sP 13 ) i nh ib ito ry in v itr o 0. 86 ± 0 .4 8 μM M CF 10 A SA RS -C oV -2 14 7 G ly cy rr hi zi n an d Li co ri ne Ly co ris ra di at e A m ar yl lid ac ea e In hi bi t C PE (v iru s- in du ce d cy to pa th ic e ffe ct ) r ep lic at io n in hi bi to r in v itr o M TS a ss ay 1 5. 07 ± 1. 2 nM 30 0 m g/ L Ve ro SA RS -C oV -2 14 8, 1 49 Ci nn am al de hy de Ci nn am om i c or te x M yr ic ac ea e Su rv iv al ra te (i n vi vo ) p ro te in sy nt he si s (in v itr o) In v iv o & in vi tro 1 in ha la tio n (5 0 m g/ ca ge / da y) 2 i no cu la tio n (2 50 μ g/ m ou se /d ay ) 2 0– 20 0 μM IC R fe m al e m ic e M D CK In flu en za A (H 1N 1 su bt yp e) 14 2 5, 7, 3 ‘, 4 ’-t et ra hy dr ox y- 2’ - ( 3, 3- di m et hy la lly l) is ofl av on e Ps or ot ha m nu s ar bo re sc en s Fa ba ce ae Vi ru ci da l a ct iv ity in v itr o 7. 1 µM Ve ro Co ro na vi ru s 14 3, 1 44 Q ue rc et in - - 3C Lp ro in hi bi to ry in v itr o 40  μ M E. c ol i B L2 1 SA RS -C oV 15 0 Ba ic al en si s Sc ut el la ria b ai ca le ns is La m ia ce ae 3C Lp ro in hi bi to ry in v itr o 0. 39 µ M Ve ro SA RS -C oV -2 15 1 Se nn os id e A Rh eu m p al m at um L . an d Rh eu m o ffi ci na le Ba ill . Po ly go na ce ae Re ve rs e Tr an sc rip ta se RN as e H R T- as so ci at ed fu nc tio ns In te gr as e in v itr o 2– 5 μM Ju rk at H IV -1 15 2 Te tr a- O -g al lo yl -β -D - gl uc os e Ch in es e he rb s - Vi ru ci da l a ct iv ity in v itr o 4. 5 M Ve ro SA RS -C oV 15 3 Lu te ol in O no po rd um il ly ric um L . As te ra ce ae RN as e H R T- as so ci at ed in v itr o 12 .8  μ M Ju rk at H IV -1 15 4 Tr yp ta nt hr in St ro bi la nt he s cu si a Ac an th ac ea e In hi bi ts e ar ly a nd la te s ta ge s of re pl ic at io n, b y bl oc ki ng v ira l R N A sy nt he si s an d pa pa in -li ke p ro te as e 2 ac tiv ity in v itr o 1. 52 µ M LL C- M K2 Co ro na vi ru s N L6 3 15 5 Te lli m ag ra nd in Eu ge ni a ca ry op hy lla ta , M yr ta ce ae Vi ru s- Ce ll Fu si on in v itr o 16 .1 2 ± 1 .9 8 m g/ m l sy nc yt ia H IV -1 15 9 G lo bo id na n A Eu ca ly pt us g lo bo id ea M yr ta ce ae H IV -1 in te gr as e ac tiv ity in v itr o 0. 64 μ M H uT 78 T -c el l H IV -1 16 0 G in kg ol ic a ci d Ch in es e he rb al m ed ic in es - in hi bi te d H IV p ro te as e ac tiv ity in v itr o 31 .2 μ g/ m l Ju rk at c el ls H IV -1 93 K ae m pf er ol d er iv at iv es - - Bl oc k th e 3a c ha nn el p ro te in s in v itr o 2. 3 µM Xe no pu s oo cy te co ro na vi ru s 15 6 Sa ik os ap on in s - - A bs or pt io n an d pe ne tr at io n of th e vi ru s in v itr o 25 m m ol /L M RC -5 co ro na vi ru s 15 8 1, 2, 3, 4, 6- pe nt a- O -g al lo yl - β- D -g lu co si de Sa xi fra ga m el an oc en tra Sa xi fra ge s In hi bi ts N S3 s er in e pr ot ea se In v itr o 0. 1- .0 01 m g/ m l Co s7 c el ls H ep at iti s C vi ru s 14 5 A rt es un at e Ar te m isi a an nu a As te ra ce ae In hi bi tio n of H IV -1 re pl ic at io n In v itr o 60 0 nM H IV -1 15 7 https://en.wikipedia.org/wiki/Myricaceae https://en.wikipedia.org/wiki/Lamiaceae https://en.wikipedia.org/wiki/Myricaceae https://en.wikipedia.org/wiki/Fabaceae https://en.wikipedia.org/wiki/Lamiaceae https://en.wikipedia.org/wiki/Polygonaceae https://en.wikipedia.org/wiki/Asteraceae https://en.wikipedia.org/wiki/Acanthaceae https://www.google.com/search?rlz=1C1GCEA_enIR901IR901&sxsrf=ALeKk02Ce63OqrNLMGVz4E_I_hPh89tgZw:1591089346063&q=Myrtaceae&stick=H4sIAAAAAAAAAONgVuLUz9U3MMxLskxfxMrpW1lUkpicmpgKAKb0cV8ZAAAA&sa=X&ved=2ahUKEwjBnZza5eLpAhWNwqYKHYx6BhsQmxMoATAeegQIERAD https://en.wikipedia.org/wiki/Myrtaceae https://www.google.com/search?sxsrf=ALeKk03CfFSNsJHH-EgW6Bn2X7a0pFv7Bg:1587287430614&q=Saxifragaceae&stick=H4sIAAAAAAAAAONgVuLUz9U3MLYwNi1-xOjMLfDyxz1hKatJa05eYzTh4grOyC93zSvJLKkUUuNig7JkuHilELo0GKS4uRBcnkWsvMGJFZlpRYnpicmpiakA-zhOm2MAAAA&sxsrf=ALeKk03CfFSNsJHH-EgW6Bn2X7a0pFv7Bg:1587287430614 https://www.google.com/search?rlz=1C1ASUC_enIR712IR712&sxsrf=ALeKk01Vqo9Cs2HASxMRzPJ2Xtx2XXJ-SA:1591684252425&q=Asteraceae&stick=H4sIAAAAAAAAAONgVmLXz9U3yDEtWsTK5VhcklqUmJyamAoACE7DjhgAAAA&sa=X&ved=2ahUKEwjI8tbzjfTpAhXBy6QKHbnrAIsQmxMoATAeegQIDBAD 17 Review A narrative review of herbal preparations against RNA virusesSaeideh Momtaz et al. J Contemp Med Sci | Vol. 7, No. 1, January-February 2021: 6 – 22 Sennoside A Sennoside A from dried roots of Rheum palmatum L. and Rheum officinale Baill is HIV-1 RT inhibitor effective phyto- chemical on both HIV-1 Reverse Transcriptase and RNase H RT-associated functions in biochemical assays. Besides, Sennoside A affected the HIV-1 integrase activity in vitro and HIV-1 replication in Jurkat cell line. Sennoside A inhibited both HIV-1 RT-associated functions with IC50 values of 2–5 μM range.152 (Table 4). Tetra-O-galloyl-β-D-glucose This small molecule from Chinese herbs exhibited prominent anti-SARS-CoV activity with a EC50 concentration of 4.5 M in Vero E6 cells153 (Table 4). Luteolin Among seven compounds isolated from Onopordum illyri- cum L., Luteolin was the most effective on HIV-1 RNase H RT-associated function in a low concentration without cyto- toxicity (IC50 of 12.8 μM)154 (Table 4). Tryptanthrin The antiviral activity of Tryptanthrin isolated from Strobilanthes cusia was investigated against coronavirus NL63 in LLC-MK2 cell line. Tryptanthrin effectively inhibited the cytopathic effect and virus yield (IC50 = 1.52 µM) in HCoV-NL63-infected cells. This molecule prevented the early and late stages of HCoV-NL63 replication, mainly by blocking the viral RNA genome synthe- sis and papain-like protease 2 activity155 (Table 4). Kaempferol derivatives These phytochemicals have a potency to block the 3a channel proteins of coronaviruses. The YxxΦ domain of 3a channel is a protein internalization signal which is involved in clath- rin-mediated endocytosis, therefore its involved in virus cell entry. In a research study, using Xenopus oocyte for heterolo- gous expression and applied voltage-clamp techniques, the gly- coside juglanin (carrying an arabinose residue) was found as the most effective kaempferol derivatives with an IC50 value of 2.3 µM for Inhibition of the 3a-mediated current156 (Table 4). Artesunate Bioingredients of Artemisia annua can play potential protective roles against infections by viruses, specifically HSV-1, HBV, HCV, bovine viral diarrhea virus, and Epstein-Barr virus. It was demonstrated that 10 days administration of artesunate (a semi-synthetic derivative of artemisinin used to treat malaria) at 600 nM inhibited HIV-1 replication157 (Table 4). Saikosaponins Among saikosaponins (A, B2, C, and D) tested on coronavirus 229E in human fetal lung fibroblasts, saikosaponin B2 demon- strated a potent anticoronaviral activity at a concentration of 25 mmol/L. Although, the mode of action of this compound possibly involved interference in the early stage of viral rep- lication such as absorption and penetration of the virus158 (Table 4). Tellimagrandin Initially, the interaction between the HIV envelope glyco- protein gp120 and the cell membrane protein CD4 results in virus-cell fusion. Out of isolated compounds from Eugenia caryophyllata, tellimagrandin significantly inhibited the virus- cell fusion and syncytia formation in HIV-1 with an IC50 value of 16.12±1.98 mg/ml159 (Table 4). Ginkgolic acid In Jurkat cells, ginkgolic acid (31.2 μg/ml) isolated from Ginkgo leaves, inhibited the HIV protease activity by 60% in a dose-dependent manner. Moreover, ginkgolic acid treatment (50 and 100 μg/ml) effectively inhibited the HIV infection at day 7 dose-dependently93 (Table 4). Globoidnan A It was reported that Globoidnan A, a lignan obtainable from Eucalyptus globoidea, can interfere with HIV-1 integrase activ- ity. This compound was found to inhibit the combined 3’ pro- cessing and strand transfer activity of HIV integrase with an IC50 = 0.64 μM160 (Table 4). Antiviral herbal medicine formulations KangBingDu KangBingDu (KBD) is a Chinese traditional medicinal formula in form of a classic oral liquid that has been modified based on the traditional Chinese “BaiHutang” and “QingWenBaiDuYin” medicine formulations. KBD is often used to improve the clin- ical symptoms of viral diseases, especially the influenza virus. KBD is composed of Radix isatidis, Rhizoma phragmitis, Radix rehmanniae, Radix curcumae, Rhizoma anemarrhenae, Rhizoma acori tatarinowii, Herba pogostemonis, Fructus forsythiae and Gypsum fibrosum. KBD significantly reduced the sensitivity of male Kunming mice to influenza viruses, which is evidenced by reduced mortality, decreased inflammation, and inhibited viral replication in the pulmonary system. In A549 cells, administra- tion of KBD increased the protein expression of MAVS (mito- chondrial antiviral signaling protein) and the levels of IFN-β protein and interferon-induced transmembrane-3 protein, resulting in inhibition of viral infection. It was shown that (R, S) -Goitrine, Mangiferine, Forsythine, and Forsythoside A were other active ingredients of KBD against the influenza virus. The mitochondrial antiviral signaling pathway was introduced as the primary mechanism of action of KBD.161 Maxingshigan–yinqiaosan In a prospective RCT, the efficacy and safety of Oseltamivir and a traditional Chinese mixture named “Maxingshigan- Yinqiaosan” in treatment of uncomplicated influenza H1N1 subtype were compared. Maxingshigan–yinqiaosan consisted of 12 herbs: Zhimahuang (honey-fried Herba Ephedrae); Zhimu (Rhizoma Anemarrhenae); Qinghao (Herba Artemisiae Annuae); Shigao (Gypsum Fibrosum); Yinhua (Flos Lonicerae Japonicae); Huangqin (Radix Scutellariae); Chaoxingren (stir-baked Semen Armeniacae Amarum); Lianqiao (Fructus Forsythiae); Bohe (Fructus Forsythiae); Zhebeimu (Bulbus Fritillariae Thunbergii); Niubangzi (Fructus Arctii Tosum); and Gancao (Radix Et Rhizoma Glycyrrhizae). Clinical interven- tions and control were given for 5 days with Oseltamivir, 75 mg twice daily; Maxingshigan–yinqiaosan, 200 mL 4 times daily. Oseltamivir and Maxingshigan–yinqiaosan, alone or together, reduced time of fever resolution in patients with H1N1 influenza.162 18 Review A narrative review of herbal preparations against RNA viruses Saeideh Momtaz et al. J Contemp Med Sci | Vol. 7, No. 1, January-February 2021: 6 – 22 Sheng Jiang San Sheng Jiang San (SJS) is a Chinese multi-herbal formulation made of four herbs consist of Rhei Radix et Rhizoma, Bombyx Batryticatus, Cicadae Periostracum, and Curcumae Longae Rhizoma. The inhibitory effect of SJS against different strains of influenza virus A/WSN/33 (H1N1) on MDCK cells was examined. The IC50 of SJS was lower than 35 μg/ml against H1N1. SJS at 2 mg/ml inhibited the NA activity up to 80%. This enzyme cleaves terminal neuraminic acid residues of gly- can structures on the surface of the infected cell, thereby facil- itating the release and spread of viruses progeny to reach the surrounding uninfected cells. The IC50 of Oseltamivir acid was 250 μM against Neuraminidase. To evaluate the efficacy of SJS in the influenza virus, infected BALB/c mice were employed as in vivo model. Oral administration of 1 g/kg/day of SJS for 7 days, exhibited 50% protection of infected mice from H1N1 symptoms. SJS also significantly down-regulated tumor necro- sis factor (TNF-α) and up-regulated IL-2 of influenza virus- induced mice.163 Lianhuaqingwen Lianhuaqingwen (LH) is another Chinese plant medicine composed of 13 herbs with positive impact on SARS-CoV-2 by inhibiting viral replication. A research study revealed that LH significantly inhibited SARS-CoV-2 replication in Vero E6 cells (600 μg/mL) and markedly reduced mRNA transcription of pro-inflammatory cytokines (TNF-α, IL-6, CCL-2/MCP-1, and CXCL-10/IP-10).164 In addition, LH in the form of cap- sule (4 capsules, thrice daily for 14 days) in patients who were suffering Covid-19 conferred therapeutic effects by improving the recovery rate of symptoms, shortening recovery time, and improving the recovery of chest radiologic abnormalities.165 San Wu Huangqin Decoction San Wu Huangqin Decoction (SWHD) is a Chinese com- pound formulation consists of Sophora flavescens, Scutellaria baicalensis, and Rehmannia glutinosa. This herbal formulation could effectively inhibit the influenza A/PR/8/34 (H1N1) virus at all steps of virus replication in vitro. The RNA expression of four H1N1 target viral proteins (hemagglutinin, NA, NP nuc- leoprotein, and matrix-2) was significantly down-regulated in MDCK cells. In vivo, SWHD at 23.40 and 11.70 g/kg signifi- cantly attenuated clinical symptoms, reduced mortality, and increased the survival time of infected animals. SWHD medi- ated the pulmonary index, viral titer, pathological changes in lung tissue, and expression of the main IFV proteins.166 Kabasura Kudineer Cresset Flare is a software that used for molecular docking studies against the spike protein SARS-CoV-2. In silico molec- ular docking assay, examining pharmacokinetics parameters, have shown that six plant species in Kabasura Kudineer for- mula (Sida acuta, Adhatoda vasica, Andrographis paniculata, Tinospora Cordifolia, Costus speciosus, Plectranthus amboni- cus) have potential to directly suppress the SARS-CoV-2 spike protein.167 Poly-herbal gel The anti-HIV activity of an aqueous gel formula containing ethanolic extract of the heartwood of Acacia catechu, leaves of Lagerstroemia speciosa, and fruits of Aegle marmelos, Phyllanthus emblica, and Terminalia chebula was examined against CXCR4 tropic and CCR5 tropic viruses. The gel inhib- ited viral activity with IC50 values of 58.17 ± 4.4 and 63.54 ± 6.8 μg/ml for CXCR4 and CCR5, respectively. CXCR4 and CCR5 are two of several chemokine receptors used by the HIV to infect T CD4+ lymphocytes. Furthermore, this gel could inhibit three key enzymes of the HIV-1 reverse transcriptase, protease, and integrase enzymes significantly.168 Qing Fei Pai Du Tang Qing Fei Pai Du Tang (QFPDT) is a Chinese medicinal prepa- ration consisting of 21 plants derivation of 5 conventional for- mula. Some studies have reported the QFPDT inhibitory effect of QFPDT on COVID-19. By several mechanisms, QFPDT could prevent the progression of mild COVID-19 cases and shorten the average duration of symptoms and hospitalization. Necessary scientific studies, supported by network pharmacol- ogy, reviewed the possible therapeutic targets of QFPDT and its constituents, including Ephedra sinica, Bupleurum chinense, Pogostemon cablin, Cinnamomum cassia, and Scutellaria bai- calensis. Their findings indicated that main herbs of QFPDT have antiviral effects via different mechanisms including direct effect on virus replication and autophagy; regulation of host pathways like Toll-like receptors, RIG-1-like helicases, AMP- activated protein kinase, phosphatidyl inositol-3-kinase/ protein kinase B or extracellular regulated kinase 1/2/mito- gen-activated protein kinase signal pathways; elevation of the human defense system via T and B cell functions, and free rad- ical scavenging activities by enhancing antioxidant enzymes. QFPDT also modulated inflammation conditions through suppression of inflammatory-related genes, signal pathways and cytokines.169 Chai-Ling Chai-Ling decoction (CLD), derived from a modification of two decoctions, include Xiao-Chai-Hu (XCH) and Wu-Ling- San (WLS) decoction, has been used to treat early-stage of COVID-19. The possible mechanisms of CLD in COVID-19 were preliminarily investigated, relying on network pharma- cology and molecular docking method. CLD might reduce the inflammatory response and improve lung damages of COVID- 19 through interleukin 17 signaling, T helper cell 17 differenti- ation, tumor necrosis factor signaling, and hypoxia-inducible factor-1 signaling. Besides, molecular docking assay indicated that beta-sitosterol, kaempferol, and stigmasterol were the pri- mary three components in CLD with the highest affinity to SARS-CoV-2 and ACE2.170 San Yao San San Yao San Fang (SYSF) was shown effective in patients with COVID-19. The synergy of SYSF and Western interventions improved the recovery rate of COVID-19 symptoms such as fever, cough, and fatigue, and other symptoms such as head- ache, gastrointestinal symptoms, myalgia, dyspnoea, and chest tightness.171 Conclusion Throughout history, humans have been dependent on plant/ natural sources for the treatment of various infections. Over the last few decades, hundreds of plant and herb spe- cies were shown to have potential antiviral activities, which 19 Review A narrative review of herbal preparations against RNA virusesSaeideh Momtaz et al. J Contemp Med Sci | Vol. 7, No. 1, January-February 2021: 6 – 22 were attributed to a variety of active phytochemicals includ- ing flavonoids, terpenoids, lignans, sulphides, polyphenolics, coumarins, saponins, furyl compounds, alkaloids, polyines, thiophenes, proteins, peptides, and some essential oils. Plant extracts or substances derived from plants possess their anti- viral effects through inhibition of viral replication and by deterring the activity of viral reproduction or interacting with vital viral proteins that are associated with virulence.172 Their ability to act as bioreactors and production of vaccines under plant platforms are another advantage of plant systems to induce mucosal or long-term immunity against viral infection. Very recently, it was proposed that highly polar glycosylated compounds and polyphenols are more effective antiviral sub- stances, particularly when being administered orally.13 In our study, we gathered information about plant extracts, essential oils, and phytochemicals that are favorable for life-threatening coronaviruses diseases and can be potential candidates for fur- ther development of antivirals. We found those plant families, including Lamiaceae, Asteraceae, and Myrtaceae contain the highest number of species with anti-coronaviruses activities, respectively. It can be suggested that the combination of these antiviral ingredients with each other, any synthetic compound, or already FDA-approved drugs or inhibitors can be a novel approach for antiviral therapies. Evaluation of efficacy and adverse effects of herbal medicines for the treatment of viral infection is warranted. Recent findings exhibited that a com- bination of herbal therapy with modern medicines signifi- cantly improved the total effective rate and syndrome score of cough, fever, dry, and sore throat, and fatigue in COVID-19 patients, signifying the advantage of herbal therapy for viral infections.173 Conflict of Interest None References 1. Sinkovics J, Horvath J, Horak A. The origin and evolution of viruses (a review). Acta Microbiol Immunol Hung. 1998;45(3-4):349-90. 2. 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