key: cord-020778-4jslid14
authors: El Sayed, Khalid A.
title: Natural Products as Antiviral Agents
date: 2007-09-02
journal: nan
DOI: 10.1016/s1572-5995(00)80051-4
sha: 
doc_id: 20778
cord_uid: 4jslid14

Since the ancient times, natural products have served as a major source of drugs. About fifty percent of today's pharmaceutical drugs are derived from natural origin. Interest in natural products as a source of new drugs is growing due to many factors that will be discussed in this article. Viruses have been resistant to therapy or prophylaxis longer than any other form of life. Currently, there are only few drugs available for the cure of viral diseases including acyclovir which is modeled on a natural product parent. In order to combat viruses which have devastating effects on humans, animals, insects, crop plants, fungi and bacteria, many research efforts have been devoted for the discovery of new antiviral natural products. Recent analysis of the number and sources of antiviral agents reported mainly in the annual reports of medicinal chemistry from 1984 to 1995 indicated that seven out of ten synthetic agents approved by FDA between 1983-1994, are modeled on a natural product parent. It has been estimated that only 5-15% of the approximately 250,000 species of higher plants have been systematically investigated for the presence of bioactive compounds while the potential of the marine environment has barely been tapped. The aim of this review is to provide an overview on the central role of natural products in the discovery and development of new antiviral drugs by displaying 340 structures of plant, marine and microbial origin that show promising in vitro antiviral activity.

Since the ancient times, natural products have served as a major sourc e of drugs. Abou t fift y percen t o f today' s pharmaceutica l drug s ar e derive d from natura l origi n [1] . Th e growin g interes t i n natura l product s a s a source o f ne w drug s ca n b e attribute d t o man y factor s includin g urgen t therapeutic needs , th e wid e rang e o f bot h chemica l structure s an d biological activitie s o f natura l secondar y metabolites , th e adequac y o f bioactive natura l product s a s biochemica l an d molecula r probes , th e development o f recen t technique s t o accuratel y detect , isolat e an d structurally.characterize th e bioactiv e natura l product s an d advance s i n solving th e deman d fo r suppl y o f comple x natura l product s [1] . Historically, th e majorit y o f th e natura l product-base d drug s includin g cyclosporine, paclitaxel and camptothecin derivatives were first discovered by traditiona l cell-base d in vitro assay s befor e thei r rea l molecula r biological targets were identified [2] . These cellular biological responses of natural products are likely to be associated wit h the inherent properties of secondary metabolites for the defense of their producing organisms [2] , Infectious vira l disease s remai n a worldwid e problem . Viruse s hav e been resistant to therapy or prophylaxis longer than any other form o f lif e due to their nature because they totally depend on the cells they infect fo r their multiplication an d survival. This peculiar characteristic has rendered the developmen t o f effectiv e antivira l chemotherapeuti c agent s ver y difficult. Currently , there are only few drugs available for the cure of viral diseases includin g acyclovi r (1) , the know n antiherpeti c dru g whic h i s modeled o n a natura l produc t parent . I n orde r t o comba t viruse s whic h have devastatin g effect s o n humans , animals , insects , cro p plants , fung i and bacteria, many research efforts hav e been devoted for the discovery of new antiviral natural products. Although the search for naturally occurrin g products whic h ca n interfer e wit h vira l infection s bega n wit h th e successful isolation of antibiotics from microorganism s but it has not been as intensive a s that of synthetic antiviral agent s [3] . This is mainly du e to the tendenc y o f most virologists wh o adop t a rational desig n o f antivira l agents rathe r tha n towar d empiricis m especiall y wit h th e progres s i n knowledge o f vira l replicatio n [3] . Moreover, ther e ar e som e problem s arising from the screening of crude extracts, as well as with the purificatio n and identificatio n o f the antivira l component s fro m thes e crud e extracts . These problems became less intense with the recent advances in differen t chromatographic an d spectroscopi c technologies . Man y natura l an d synthetic compound s wer e foun d t o sho w in vitro antivira l activit y bu t were much les s effective whe n tested in vivo. Thi s could be attributed t o difficulty i n dru g transportatio n t o th e cell s o f th e infecte d tissu e especially i f thes e tissue s becom e inflamme d du e t o infection . Man y antivirally activ e compound s ar e to o toxi c fo r therapeuti c applications . However, natura l product s remai n th e bes t resourc e fo r chemicall y diversed ne w lea d entitie s tha t coul d serv e fo r futur e developmen t a s potent and safe antiviral agents. Recent analysis of the number and sources of antivira l agent s reporte d mainl y i n th e annua l report s o f medicina l chemistry fro m 198 4 t o 199 5 indicate d tha t seve n ou t ofte n syntheti c agents approve d b y FD A betwee n 1983-1994 , ar e modele d o n a natura l product paren t [4] . Thes e drug s are : famciclovi r (2) , ganciclovi r (3) , sorivudine (6) , zidovudin e (7) , didanosin e (8) , zalcitabin e (9 ) an d stavudine (10) [4] .

The aim of this review is to provide an overview on the central role of natural products in the discovery and development of new antiviral drugs.

The original Latin meaning of "virus" is "poison", "venom" or "slime" [5] . The word "virus " was also used figuratively i n the sense of "virulen t or bitter feeling", "stench" or "offensive odor " [3] . In the late 1800s, the term "virus" was bestowed on a newly discovered class of pathogens, smaller than bacteria being studied by Louis Pasteur and others of that era [6] . As late as 1907 , "virus" was defined a s "the poison of an infectious diseas e especially foun d i n th e secretio n o r tissue s o f a n individua l o r anima l suffering fro m infectious diseases [5] . In the early decades of the twentieth century, viruses were identified a s infectious agent s that were filterabl e and invisibl e i n the ligh t microscop e whic h superficiall y distinguishe d them from most familiar microorganisms [5] . Today, viruses are defined as noncellular infectiou s agent s that vary in size, morphology, complexity , host range and how they affect thei r hosts [7] . However, they share three main characteristics in common: a) A virus consists of a genome, either RNA o r DN A cor e (it s geneti c material ) whic h i s surrounde d b y a protective protei n shell . Frequentl y thi s shel l i s enclose d insid e a n envelope (capsid) that contains both proteins and lipids, b) A virus can be replicated (multiplied ) onl y afte r it s genetic materia l enter s a host cell . Viruses are absolutely dependen t o n the host cells' energy-yieldin g an d protein-synthesizing machinerie s an d henc e the y ar e parasite s a t th e genetic level, c) A virus's multiplication cycle includes the separation of its genomes from its protective shells as an initial step [7] . When a virus is outside the host cell, it is considered no more alive than a chromosome [6] .

The interval between successive mitosis of the individual cell is divided into three periods [7] : 1-Th e Gl perio d precedes DNA replication. Its average duration is 12 hours. 2-Th e S period during which DNA replicates. Its average duration is 8 hours. 3-Th e G2 period i n which the cell prepares for th e next mitosis. Its average duration is 4 hours.

RNA an d protei n ar e no t synthesize d whil e mitosi s proceeds , i.e. , during th e metaphas e whic h i s betwee n 0 2 an d G l period s bu t ar e otherwise synthesize d throughou t th e multiplicatio n cycl e [7] . Nongrowing cell s are usually arreste d i n the Gl period ; the resting stat e i s referred t o a s GO. Under norma l grov^h conditions , cells o f a growing culture multiply in an unsynchronized manner, hence cells at all stages of the cycle are present. The aging of cells starts after abou t 50 passages by D slowing their growth rate. The amount of time they spend in GO after eac h mitosis gradually increases . The chromosomal complemen t change s fro m normal diploi d t o aneuploid pattern , supernumerar y chromosome s an d i t finally fragmente d an d th e cel l dies . Malignan t tissue s giv e ris e t o aneuploid cel l line s tha t hav e infinit e lif e span s an d ar e know n a s continuous cell lines.

The main feature of normal animal cell is its compartmentalization [7] . The DNA o f the animal cel l i s restricted to the nucleus at all cell cycle stage s except durin g metaphas e whe n no nucleus exists . The synthesi s o f RN A occurs i n the nucleu s an d mos t o f i t remains there , but messenge r RN A and transfe r RN A migrat e t o th e cytoplasm . Ribosoma l RN A i s synthesized i n th e nucleolus ; th e tw o ribosoma l subunit s ar e partl y assembled in the nucleolus and nucleus then migrate to the cytoplasm. All protein synthesi s procee d i n th e cytoplasm . Th e mitochondria , whic h i s located onl y i n th e cytoplasm , contain s DNA-s , RNA -an d proteinsynthesizing system s of their own [7] .

Viruses replicate in different ways . In all cases, the viral DNA or RNA i s copied repeatedly. Viral proteins are synthesized inside a suitable host cell where man y ne w vira l particle s ar e assemble d [6] . Generall y viruse s replicate through the following stage s [3, 6, 7] , whic h ar e incorporate d int o th e host' s plasm a  membrane.  4-Thes e viral nucleic acids, enzymes and capsid proteins are assembled into ne w vira l particle s (genomes ) togethe r wit h thei r associate d RNA or DNA polymerase. 5-Th e newly formed viral particles are released from the infected cell.

Viruses usually replicat e by lytic or temperate pathways. In the lytic pathway, stages 1-4 from above proceeds quickly and the virus is released as the host cells undergo lysis, ruptures and dies after los s of its contents.

In temperat e pathways , th e viru s doe s no t kil l th e hos t cel l bu t th e infection enter s a period of latency, in which viral genes remain inactive inside th e hos t cell . I n som e case s o f latenc y th e vira l gene s becom e integrated into the host's DNA, replicated along with it and passed along to all daughter cells. In time, damage to the DNA or some other event may activate transcription of the viral genes therefore new viral particles can be produced an d infected cell s are destroyed [6] . Proposed targets of some specific antivira l chemotherap y ar e illustrate d i n Figur e 1 and ca n b e summarized as [3] :

1-Attachmen t (adsorption) of the viral particle to the host cell. 2-Penetratio n of the host cell by infectious viral particles. 3-Particle s uncoating, release and transport o f viral nucleic acid and core proteins. 4-Nuclei c acid polymerase release and/or activation. 5-Translatio n of m-RNA to polypeptides which are early proteins. 6-Transcriptio n of m-RNA. 7-Replicatio n of nucleic acids. 8-Protei n synthesis (late proteins). 9-Vira l polypeptides cleavage into useful polypeptides for maturation. 10-Morphogenesi s and assemblage of viral capsids and precursors. 11-Encapsidatio n of nucleic acid. 12-Envelopment. 13-Release.

Proteins represen t th e mai n vira l component . Protein s ar e th e sol e constituent o f capsids, the major componen t of envelopes and also they are associated with the nucleic acids of many viruses as core proteins [7] . Viral proteins have a wide range of molecular weight ranging from 10,000-150,000 daltons. Viral proteins also vary in number, some viruses posses as few as three species while others contains up to 50 protein species. All members o f th e sam e viru s famil y displa y almos t th e sam e highl y characteristic electrophoretic protein patterns [7] .

Glycoproteins: Vira l envelope s usuall y contai n glycopotein s i n th e form o f oligomeric spike s or projections. Th e carbohydrate moietie s of glycoproteins are formed o f oligosaccharide (10-15 monosaccharide units) which are linked to the polypeptide backbone through N-and O-glycosidi c bonds involvin g asparagin e an d serin e o r threonine , respectively . Thei r main component s are : galactos e an d galactosamine , glucos e an d glucoseamine, fucose , mannos e an d siali c aci d whic h alway s occupie s a terminal position [7] .

Example of some viral proteins with specialized functions are : Hemagglutinins: Man y anima l viruse s (e.g. , ortho -an d paramyxoviruses) agglutinate the red blood cells of certain animal species. This mean s tha t thes e re d cell s contai n receptor s fo r certai n surfac e components of viral particles that act as cell attachment proteins which are glycoproteins and known as hemagglutinins. Viral hemagglutinins could be used in their quantitative measurement [7] .

Enzymes: Anima l vira l particle s ofte n contai n enzyme s (Tabl e 1) . These enzymes are virus-specific. I n addition to the enzymes summarize d in Tabl e 1 , viruse s ofte n contai n othe r enzymes . Amon g the m ar e th e enzymes tha t modif y bot h end s o f m-RN A molecule s synthesize d b y their cappin g enzyme s an d poly(A ) polymerases . Protei n kinases , deoxyribonucleases, DNA-dependen t phosphohydrolase s an d topoisomerases are also often present in viruses [7] .

Homeostasis of cell numbers in multicellular organisms is maintained by a balance betwee n cel l proliferatio n an d physiologi c (programmed ) cel l death. Apoptosis is a process by which cells undergo physiologic death in response t o a stimulu s an d i t i s a predictabl e serie s o f morphologicall y defined events . It is divided int o two stages namely, the breakdown of the nucleus an d alteratio n o f th e cel l shap e an d th e plasm a membran e permeability. Th e consequence s o f apoptosi s ar e th e fragmentatio n o f nuclear DNA , the zeiosi s (boiling ) o f the cytoplas m associate d wit h th e blebbing and increased granularity of the plasma membrane and fracturin g of the cel l int o subcellula r DNA-containin g apoptoti c bodies . Apoptosi s process i s different fro m necroti c cell death by involvement o f lysosoma l enzyme leakage into the cytoplasm, the swelling of the cell and the actual rupture of the plasma membrane. Necrosis is often induce d by agents that affect membran e integrity , generalize d protei n synthesis , o r energ y metabolism [9] . Apoptosis ca n b e induced*b y a variet y o f stimuli , e.g. , steroids, cytokines, DNA-damaging agents , growth factor withdrawa l an d in case o f T or B cells, antigen-receptor engagement . Apoptosi s i s also a mechanism b y whic h cytotoxi c lymphocyte s kil l thei r targets . Man y viruses ca n induc e apoptosi s i n infecte d cell s whil e man y othe r viruse s especially transformin g viruses , ca n inhibi t apoptosi s an d allo w fo r cel l transformation. Th e nuclea r change s durin g apoptosi s induc e chromati n [6] .

Viruses caus e severa l hundre d infectiou s disease s t o man y plant s afte r successfully penetratin g their cell walls, reducing the yield of a variety o f crops includin g tobacco , potatoes , tomatoes , a s wel l a s man y othe r vegetables, inducin g seriou s economi c damages . Som e insect s tha t fee d plants assis t i n vira l infection . Vira l particle s ma y b e clingin g t o thes e insects' piercing or sucking devices and when these devices penetrate plant cells, infectio n occurs . 

Many anima l viruse s infec t human s an d animal s causin g severa l seriou s diseases. Tabl e 2 present s a summar y o f som e anima l viruse s an d th e diseases they induce.

Viroids ar e plant pathogen s whic h consis t o f naked strand s o r circle s o f RNA with no protein coat. Viroids are mere snippets of genes smaller than the smalles t know n vira l DN A o r RN A molecul e an d the y ca n hav e damaging effect s o n citrus , avocados , potatoe s an d othe r cro p plants .

Apparently, enzyme s alread y presen t i n a hos t cel l synthesiz e viroi d RNA then use this new viroid RNA as a template for building new viroids. Some unidentified infectiou s agents cause some rare fatal diseases of the nervous system including Scrapie in sheep and Kuru and Crutzfeldt-Jaco b (mad cow ) diseas e i n humans . Probabl y thes e disease s ar e cause d b y infectious protei n particles , tentativel y name d prions . Prion s migh t b e synthesized accordin g t o informatio n i n mutate d genes . Researcher s studying scrapie , hav e isolate d th e gen e codin g fo r altere d form s o f a protein in infected cells [6] .

Viruses are either measured as infectious units, i.e., in terms of their ability to infect, multipl y an d produce progeny or as viral particles, regardless of their function a s infectious agents [7] .

Titration mean s th e measuremen t o f the amoun t o f viru s i n terms o f th e number of infectious unites per unit volume.

Plaque Formation [7 ] Monolayers of susceptible cells are inoculated with small aliquots of serial dilutions o f th e viru s suspensio n t o be titrated. Wheneve r vira l particle s infect cells, progeny virus particles are produced, released and immediately infect adjoinin g cells . This process i s repeated until after 2-1 2 incubatio n days o r more . Area s o f infecte d cell s develo p plaque s tha t ca n b e see n with a naked eye. Agar is frequently incorporate d i n the medium to ensure that th e liberate d progen y viru s particle s i n th e mediu m d o no t diffus e away an d initiat e separat e o r secondar y plaques . The infecte d cell s mus t differ i n some recognizable manner from non infected ones , i.e., they must be completely destroyed, become detached from the surface o n which they grow o r possess stainin g properties differen t fro m thos e o f normal cells . The mos t commo n metho d t o visualize plaques i s to apply neutra l re d o r crystal violet to the infected cel l monolayers and then counting the number of no n staine d area s [7] . Titer s ar e expresse d i n term s o f numbe r o f plaque-forming unit s (PFU ) pe r milliliter . Ther e i s a linea r relationshi p (linear dose-response curve ) between the amount of virus and the numbe r of plaque s produce d whic h indicate s tha t eac h plaqu e i s produced b y a single vira l particle . Th e viru s progeny i n eac h plaqu e ar e clones . Viru s stocks derived fro m singl e plaques are named "plaqu e purified " whic h i s important i n isolatin g pur e viru s strains . Plaqu e formatio n i s th e mos t desirable metho d o f viral titration becaus e i t is economic an d technicall y simple. However, not all viruses can be measured thi s way due to lack of host cells that can develop the desired cytopathic effects (CPE) . 

Many anima l viruse s ge t adsorbe d b y red bloo d cell s (RBCs ) o f variou s animal species. Each viral particle is a multivalent, i.e., it can adsorb more than on e cel l a t a time . I n practice , th e maximu m numbe r o f cell s wit h which any particular virus can combine is two since RBCs are bigger than viral particles. In a virus-cell mixture in which the number of cells exceeds the number of viral particles, the small number o f cell dimer that may b e formed i s generally undetectable . If the number o f viral particles exceed s the number of cells, a lattice of agglutinated cells is formed tha t settles out D in a characteristic readily distinguishable manner from th e settling pattern exhibited b y unagglutinate d cell s [7] . Hemagglutinatio n assa y i s th e determination o f the virus that will exactly agglutinate a standard numbe r of RBCs. Because the number of viral particles required fo r this is readily calculated (slightly higher than the number of cells), hemagglutination is a highly accurate and rapid assay.

In Vitro Antiviral Screening Assays [11, 12] The vira l infectivit y i n culture d cell s i s determine d durin g viru s multiplication i n the presenc e o f a singl e teste d compoun d o r extrac t o r after extracellular incubation. Current Antiviral Chemotherapy [13, 14] Research i n antiviral chemotherapy starte d around early 1950' s when the search fo r anticance r drug s revealed severa l new compounds tha t inhibi t viral DN A synthesis , e.g. , th e pyrimidine analo g idoxuridin e whic h wa s later approve d a s a topica l treatmen t fo r herpe s keratitis . Sinc e then , research effort s wer e focused o n both purine and pyrimidine nucleosid e analogs [13] . With the emergence of AIDS epidemic, research on antiviral generally an d specificall y anti-HI V becam e highes t priority . Man y o f these retrovirus proteins have been purified and characterized for the sake of designing drugs that would selectively inhibit some critical enzymes of HIV such as reverse transcriptase and protease which are required for the final packaging of this virus particle. 1-Zidovudin e (7 ) (previousl y azidothymidine , AZT ) i s a deoxythymidine analo g tha t als o requires anaboli c phosphorylatio n for activation . I t competitivel y inhibit s deoxythymidin e triphosphate fo r th e RT . I t als o act s a s a chai n terminato r i n th e synthesis of pro viral DNA. It is active against HIV-1, HIV-2 and the

human T cell lymphotropi c viruses . Resistance to 7 occurs due to mutation in RT gene. Didanosine (8 ) i s a syntheti c analo g o f deoxyadenosine . I t i s anabolically activated to 2,3-dideoxyadenosine-5-triphosphate which inhibits viral replication as 7. Resistance is typically associated with mutation at codon 74.

Zalcitabine (9) is a pyrimidine nucleoside that inhibits replication of HIV-1 in a similar mechanism to 7. Mutation at codon 65 induces resistance which is associated with the decrease in susceptibility to 8 and 9. 4-Stavudin e (10) is a thymidine analog that also requires a metabolic activation as that of 7. It is active against HIV-1. 5-Lamivudin e (11) is a nucleoside analog which in vitro inhibits HIV-1 and HBV . It inhibits HIV-RT and shows synergistic effec t wit h 7 against HIV-1 . It requires metabolic phosphorylation a s that of 7.

High level of resistance is developed by mutation at codon 184.

1-Indinavi r is a specific inhibitor of HIV-1 protease which is essential for th e production o f mature and infectious virions . It i s currently clinically approved for treatment of HIV-1 infections. 2-Ritonavi r is an inhibitor of HIV protease with high bioavailability. It is metabolized by the hepatic P450 cytochrome oxidase system and hence suffers from several drug interactions. 3-Saquinavi r is a synthetic peptide-like analog that inhibits the activity of HIV-1 protease and prevents the cleavage of viral polyproteins. 3-Ribaviri n [13 ] i s a guanosin e analo g tha t i s intracellularl y phosphorylated b y the host cell's enzymes . Despite its mechanism is not yet fully elucidated , it apparently interferes with the synthesis of guanosin e triphosphat e t o inhibi t cappin g o f vira l mRN A an d some viral RNA-dependent polymerases. Its triphosphate derivative inhibits the replication o f a wide range o f RNA and DNA viruses including influenz a A and B , parainfluenza, respirator y syncytia l virus (RSV), paramyxovirus, HCV and HIV-1.

Four basi c approache s ar e conducte d fo r plan t selectio n fo r antivira l screening assays : 1 -Rando m collectio n o f plant s followe d b y mas s screening. 2-Ethnomedical approach. 3-Literature-based follow up of the existing leads. 4-Chemotaxonomic approac h [12] . The second and third approaches ar e th e mos t favore d one s becaus e o f thei r cost-effectiv e applicability. The selection based on folkloric use proved five times higher percentage o f active leads than other approaches. The random approach usually affords mor e novel compounds with antiviral activity. Combining ethnomedical, phytochemical an d taxonomical approache s is considered the best compromise.

Different cel l culture-base d assay s ar e currentl y availabl e an d ca n b e successfully applie d fo r plan t extract s an d pur e compounds . Antivira l agents tha t interfer e wit h on e o r mor e vira l biosyntheti c dynami c processes are good candidates as clinically useful drugs . Virucidal agents that extracellularl y inactivat e viru s infectivit y ar e rathe r candidate s a s antiseptics. Th e ke y factor s tha t determin e th e selectio n o f th e assa y system are : simplicity , accuracy , reproducibility , selectivit y an d specificity [12] . After evaluatio n o f th e antivira l potenc y o f a teste d compound along with its cytotoxicity, the therapeutic index in a given viral system i s calculated. Th e therapeutic inde x i s defined a s a ratio o f the maximum drug concentration at which 50% of the normal cells grovrth is inhibited to the minimum drug concentration at which 50% (sometimes 90 or 99%) of the virus is inhibited. The relative potency of a new antiviral agent should be compared with an existing approved drug.

In vivo testing of any new in vitro active antiviral agen t i s considered th e key ste p befor e an y huma n clinica l trials . Thi s mode l shoul d predic with an animal's metabolic processes. 4-Provin g tha t the compoun d wil l resist an d will no t adversel y affec t the immune system [12] .

Two usefu l anima l model s ar e usuall y employed : heterologu s o r homologus. In heterologus systems, a disease is induced by a virus from a n animal origi n i n an experimenta l anima l tha t mimic s th e huma n disease . Several review s hav e bee n publishe d dealin g wit h natura l productsderived antivira l compound s [11, 12, [16] [17] [18] [19] [20] [21] [22] [23] . Presently, there ar e only tw o plant-derived compounds under clinical development [2] . (-f)-Calanolide A (12) i s a C2 2 coumari n isolate d fro m th e Malaysia n rainfores t tree , Calophyllum langigerum b y th e U.S . National Cance r Institut e [2] . I t shows a poten t HIV-R T inhibitor y activit y [2] . In vitro studie s o f 1 2 demonstrated activit y agains t HIV-1 includin g AZ T an d othe r nonnucleoside R T inhibitors-resistan t strains . It als o show s synergisti c anti -HIV activity i n combination with nucleoside RT inhibitors: 7, 8 and 9 [2] . To overcom e th e difficult y o f suppl y o f 12 , its tota l chemica l synthesi s was accomplishe d [2] . I n Jun e 1997 , clinica l developmen t o f 1 2 wa s started as a potential drug for treatment of AIDS. A single -center 7-mont h U.S. phas e l a clinica l tria l o f 1 2 wa s starte d t o asses s it s safet y an d tolerability [2] , SP-30 3 (13 ) i s a mixtur e o f natura l oligomeri c proanthocyanidins u p to a molecular weigh t 2100 daltons. It is isolated from th e late x o f a Latin America n plan t Croton lechleri [2] , It show s potent in vitro activity against HSV and other varieties of DNA and RNA viruses. Virend, whic h i s the topical formulatio n o f 13 , is evaluated i n phase II clinical trials for the treatment of genital herpes in combination with acyclovir. These trials were later suspended as they proved virend to have no additional benefit over using oral acyclovir alone. Provir, the oral formulation o f SF-SOB, is proved to be safe and well tolerated in phase I trials but ineffective i n phase II for the treatment of RSV since there was no adequate absorption by patients. However, provir was proved effectiv e in symptomati c treatmen t o f traveler' s diarrhe a throug h restoratio n o f normal bowel function and prevention of recurrences [2] . 

Alkaloids are heterogeneous group of compounds linked by the common possession o f a basi c nature , containin g on e o r mor e nitroge n atom s usually in combinations part of heterocyclic system [11] , Their precursors are usually amino acids and they exert certain biological activities. Many alkaloids are also foun d i n animals and humans where they coul d exer t a profound pharmacologica l activit y [11] . Tabl e 1 illustrate s variou s alkaloids with activity against many animal viruses. 

Lycorine (16), Pretazettine (17) ApQrphing;

Oliverine (18),

PgnzQphgnanthriding:

Chelidonine (21) 

Schumannificine (29 ) FlavQiioid: 

Opium;

Morphine (34) , Codeine (35), Papaverine (36 ) Phenantl iroquinozolizidine:

Cryptopleurine (37 ) Pipgriding;

1-Deoxynojirimycin (38) , l -Deoxymannojirimycin (39) , a-Homonojirimycin (40 ) Protoberberine:

Berberine (41) , Columbamin e 1 (42) , Palmatine (43) Pvrrolizidine:

1 Austra l ine (44 ) Ouinoline/Isoquinoline: Table 4 summarizes the antiviral activity of plant and some non-plant carbohydrates. 

Chromones, furanocoumarins an d flavonoids ar e common constituent s i n many plan t families . Coumarin s ar e specifically abundan t i n the familie s Rutaceae an d Umbellifera e [11] . The yield coul d sometime s reac h u p t o 1% o f the dr y plant weight . Tabl e 5 illustrates various antivira l activitie s of chromones, coumarins and flavonoids. 

Lignans ar e widesprea d secondar y metabolite s i n plant kingdom . The y occur in many parts of plants especially wood, resin and bark trees [11] . They are also found i n many roots, leaves, flowers, fruits an d seeds [61] .

There is an evidence that lignans play a major rol e in plant-plant, plantinsect an d plant-fungu s interaction s [11] . The chemica l structure s o f T e r m i l i g n a n ( 1 0 4 ) , T h a n n i l i g n a n ( 1 0 5 ) , Anolignan (106 ) Justicidin A (107) [89] lignans ar e divers e an d comple x despit e the y ar e essentiall y dimer s o f phenylpropanoid unit s (C6-C3 ) linked by the central carbons of their sid e chains [11] . Presently, there are six lignan subgroups : butane derivatives , lignanolicles (butanolides) , monoepoxylignan s (tetrahydrofura n derivatives), bisepoxylignans (3,7-dioxabicyclo(3.3.0)-octane derivatives) , cyclolignans (tetrahydronaphthalenes ) an d cyclolignan s base d o n naphthalene [11] . Phenolics, benzoquinones , naphthoquinones , anthraquinones and phenylpropanoids ar e abundant secondary metabolite s in plants. Table 6 illustrates the reported antivira l activitie s of these plan t secondary metabolites. 

Tannins ar e phenoli c compound s tha t ar e abundan t i n plan t kingdom . Basically, ther e ar e tw o type s o f tannins . Hydrolysabl e typ e whic h usually consists of simple phenolic acids, e.g., gallic acid, which is linked to sugar . Th e condense d typ e i s simila r t o flavonoids . Th e know n medicinal tannin-containin g plan t lemo n bal m (Melissa officinalis, Labiatae) is extensively studied as antiviral agent [11] . Leave s of this plant contain abou t 5% , dry weight o f tannins which ar e mainly constructe d from caffei c acid . A cream containing 1 % of a specially prepare d dried extract from lemon balm leaves has been introduced to the German market for loca l therap y o f herpes infection o f the ski n [90] . The effect o f this cream i n th e topica l treatmen t i s statisticall y significan t a s proven b y clinical studies [90] . This is a decisive indication that constituents and /or extracts of plants could serve as useful lead s for developing the antiviral drugs for the future. Terpenoids are also abundant secondary metabolites Condensed tannins: CatgghinJg aci d (156 ) condense d t a n n i n s , P a v e t a n n i n s , Cinnamtannins. 1 Galloy l catechi n an d epicatechin .

Procyanidin B 2 (157), [29] in plant world. Terpenoids are essentially derived from the basic 5-carbons isoprene unit . Thes e ar e classifie d into : monoterpene s (CIO) , sesquiterpenes (CI5) , diterpene s (C20) , triterpenes , sterols , saponins . 

About seve n hundre d polyacetylene s hav e bee n isolate d s o fa r mainl y from plant s belongin g t o th e famil y o f Asteraceae , Umbellifera e an d Campanulaceae [11] . Polyacetylenes occu r principally a s straight chai n polyines, allenes , phenyl, thiophenyl , thioether an d spiroketal-enoethe r derivatives in a quite high yield. Thiophenes and related sulfur compounds are usuall y groupe d togethe r wit h th e polyacetylene s becaus e o f thei r common biosyntheti c pathway s [11] . Few plant-derive d lactones , butenolides an d phospholipid s sho w antivira l activity . Th e antivira l activities o f thiophenes , polyacetylenes , lactones , butenolide s an d phospholipids from plant origin are reported in table 8. 

Thiarubine A (190)

Thiophene-A (191) Phenylheptatriyne ( [11] . Additional proteins (PAP-II an d PAPs) were found i n relative smaller amounts. Subsequently, other RIPs were found i n other plants and exhibit similar antiviral activity, e.g., tritin fro m Triticum aestivum seed , geloni n fro m Gelonium multiflorum seed , momordin fro m Momordica charantia seed , sapori n fro m Saponaria officinalis seed , dianthin fro m Dianthus caryophyllus leaf , tricosanthi n from Trichosanthes kirilowii [11] , bryodin 2 from Bryonia dioica [129 ] and Bougainvillea antivira l protei n I (BA P I ) fro m Bougainvillea spectabilis roo t [130] . 

Some varieties of Nicotiana glutinosa produce a protein called AVF which afford som e protectio n agains t TM V b y restrictin g it s lesion s i n a n analogy manne r t o interferon s [11] . AV F I s a glycoprotei n whic h i s terminally phosphorylate d wit h 22,00 0 dalton s molecula r weight . Th e mechanism of action of AVF is not yet established.

Meliacin i s a n antivira l glycopeptid e o f molecula r weigh t 5000-600 0 daltons, isolated from th e leaves of Melia azedarach (Meliacea ) [11, 134] .

Its 

Aprotinine i s anothe r plant-derive d antivira l polypeptid e whic h specifically inhibi t myxoviruse s especiall y influenz a A . Aportinin e i s known to be a protease inhibitor . It acts by interferin g wit h the essentia l step of cleavage of the precursor Hao into subunit polypeptides and hence prevents the viral infection [11] .

Many plant-derive d di -and tri-peptides wer e proved to be active agains t HSV an d measle s viru s (MV) . Thes e peptide s consis t mainl y o f carbobenzoxy derivative s o f phenylalanin e [11] . Cationi c peptide s ar e used as nature's antibiotics, being produced i n response to an infection i n virtually mos t organism s includin g plant s an d insects . Cationi c peptide s and protein s ar e no w proceedin g throug h clinica l trial s a s topica l antibiotics and antiendotoxins [136] .

Several thousan d plan t extract s hav e bee n show n t o posses s in vitro antiviral activit y wit h littl e overla p i n specie s betwee n studies . I n mos t cases, th e assa y method s ar e designe d t o detec t virucidal , prophylacti c [11] [11] [11] [11] [11] [11] [11] [11] [11] [11] [11] [11] [11] [11]

[11] [11] activities an d t o defin e extract s tha t interfer e w^it h vira l replicatio n i n cultured cells . Aqueous an d organi c extract s have generall y bee n prove d equally fruitfu l an d hence i t is not feasible t o asser t that an y on e metho d of extractio n i s preferable . Furthe r characterizatio n o f th e activ e constituents in these active extracts should reveal some useful compounds . Many o f activ e extract s ma y tur n ou t t o b e identica l o r relate d t o th e previously describe d structure classes. Yet, there also may be a possibility for som e nove l phytochemicals . Tabl e 9 summarize s som e o f th e mos t active extracts in the literature.

With marin e specie s comprisin g approximatel y on e hal f o f tota l globa l biodiversity fo r whic h estimate s rang e betwee n 3-50 0 x 10^ specie s o f prokaryote and eukaryote organisms. The marine macrofauna represent s a broader rang e of taxonomic diversit y than found i n terrestrial evironmen t [150] . With a typical eukaryote possessing 50,000 genes, the global marine macrofauna ar e the source of 2.5 x 10^^ -1.5 x 101^ primary products an d an associate d extensiv e rang e o f secondar y metabolite s [150] . Presently, Only fe w thousan d nove l compound s fro m marin e origi n hav e bee n identified. Thes e compounds have been revealed unique in chemical and pharmacological terms . However, onl y fe w promising therapeuti c lead s 

Many marine-derived peptides, alkaloids, proteins, nucleosides and other A^-containing compound s were show n to be active agains t severa l vira l species. Table 10 illustrates these activities.

The antiviral activities of various marine-derived terpenoids, steroids and carotenoids are summarized in Table 11 . 

Halogenated cyclohexadienone (245) Sggqviitgrpgngs:

Avarol (246) [188] [189] [190] [191] [192] [193] [194] [195] [196] [197] [198] [199] [200] [201] [202] [203] [204] ( Table 11 ) . contd.. [217] .

A polysaccharide from the green marine alga Ulva lactuca inhibited the reproduction of many human and avian influenza viruses . Acid hydrolysi s of thi s polysaccharid e reveale d th e presenc e o f arabinose , xylose , rhamnose, galactose , mannos e an d glucos e i n rati o o f 1:1:9:5:2:5:16 , respectively along with an unidentified suga r [218] .

Treatment o f laminari n isolate d fro m th e marin e alg a Laminaria cichorioides b y endo-p-l,3-glucanas e fro m marin e invertebrate s transformed p-l,3:l,6-gluca n int o a highl y efficien t preparatio n agains t tobacco mosai c virus named antivi r [219] . Polysaccharides, compose d o f mannose, galactose, glucose, uronic acid and sulfate group s (7-8% wt/wt) was obtained from the marine microalga Cochlodinium polykrikoides sho w potent inhibitor y activitie s against : influenz a viruse s typ e A an d B , respiratory syncytia l viruse s typ e A an d B , HIV-1 , HSV-1 an d parainfluenza viruse s typ e 2 and 3 . No cytotoxicit y no r inhibitio n t o th e blood coagulation were observed up to 10 0 |Lig/mL [220] .

An unusua l sulfate d mannos e homopolysaccharide , isolate d fro m th e Pacific tunicat e Didemnum molle show s in vitro anti-HI V activity . Th e NMR dat a of this polysaccharide reveal s that it consists o f a sequence o f 2,3-disulfated mannos e unit s joined throug h p (1,6 ) glycosidi c linkage s [221] . A natural sulfate d mucopolysaccharid e (OKU40) , extracted fro m a marine plan t Dinoflagellata an d a n artificia l sulfate d polysaccharid e (0KU41), was prepared fro m a marine Pseudomonas, displaye d antivira l activities agains t HIV-1 an d -2 , zidovudine-resistan t HIV-1 , HSV-1 , influenza viruse s A an d B , respiratory syncytia l viru s an d measle s viru s without displayin g cytotoxicit y o r inhibition o f blood coagulatio n o f host cells [222] . Table 1 2 illustrates the reported antiviral activities of the common marin e secondary metabolite s polyacetylenes , quinones/pyrones , macrolide s an d prostaglandins. 

The human dream of finding a n antiviral antibiotic from microbial origin which selectively affects the viral but not the host cell in a similar manner to th e regula r antibiotic s ha s no t becom e a reality . However , severa l microbial-derived metabolite s sho w promisin g activity . Th e us e o f microbes t o modif y syntheti c compound s o r t o accomplis h specifi c desired reactio n i s commo n i n pharmaceutica l industry . Adenin e arabinoside (Ara A, 200) , which is approved for clinical investigation, is also produce d b y a Streptomyces s p [19] . Example s o f secondar y metabolites fro m microbia l origi n tha t sho w antivira l activitie s ar e presented below.

Rifamycins ar e microbial-derived macrolide s that were isolated i n 195 7 from the actinomycete Streptomyces mediterranei, obtained from the soil of the pine forests of southern France [18] . Of these, rifamycin B (306) is the leas t toxic . Additio n o f diethylbarbituri c aci d t o th e fermentatio n medium result s i n th e productio n o f 30 6 only . Rifampici n i s th e C3hydazone semisyntheti c derivativ e o f rifamycins . Rifamycin s sho w in vitro and in vivo anti-poxyviruses, e.g., VV activities [18] . These activities are apparently du e to inhibition of the early step of viral morphogenesi s which affect s th e assembl y o f immatur e vira l particles . The inhibitor y activity of rifamycins o n retroviruses is also reported [18] . Many natural and semisyntheti c rifamycin s inhibi t th e virio n RNA-dependen t DN A polymerase (RT ) [18] . Rifamycin B (306) wa s reported activ e agains t murine sarcom a viru s (MSV ) du e t o it s RT , focu s formatio n an d cel l transformation inhibitor y activities [18] . Rifamycin antibiotics also inhibit the RT of Rauuscher leukemia virus, preventing its leukomogenic activity [18] .

Streptovaricin B (307), tolypomycin an d geldanamycin ar e examples of ansamycins whic h ar e chemicall y relate d t o rifamycins . Th e streptovaricins an d tolypomycin s resembl e rifamycins i n RT-inhibitor y activity [18] . Streptovaricin B inhibits the replication o f poxviruses by inhibiting earl y stage s o f mRN A synthesi s [18] . Inhibitio n o f focu s formation of MSV by streptovaricins is also reported [18] .

Gliotoxin (308) is a fungal metabolite , isolated from Aspergillus terreus and foun d t o hav e antibacterial , antitumo r an d antifunga l effect s [18] . Gliotoxin acetate inhibited the CPE of poliovirus in monkey kidney cell cultures due to the early stag e inhibition o f RNA viral replication [18] . Gliotoxin also inhibits influenza virus-induced RNA polymerase. Arantonins are related compounds, isolated from Arachniotus aureus diXidi Aspergillus terreus and show RT inhibitory activity [19] . The activity is attributed to the epidithiapiperazinedione moiety, as the case of 308.

Sporidesmin 

Distamycin A (309 ) i s a n oligopeptide , isolate d fro m Streptomyces distallicus that inhibits transcription and replication of DNA viruses along with its other related semisynthetic analogs [18] . Example of DNA viruses inhibited by this group are vaccinia virus and HSV-1. Distamycin A also shows inhibitory activity for RT of retroviruses [18] .

Daunomycin (310 ) and doxorubicin (311 ) are anthracycline glycosides , isolated from Streptomyces peucetius [18] . These compounds are used in cancer chemotherapy du e to their ability to bind DNA. Both compounds inhibit RT and production of murine leukemia virus [18] . 

Actinomycin D is a peptide antibiotic, produced by Streptomyces parvulu. It interacts with cellular DNA and inhibits the replication of mammalian viruses tha t depen d o n cellula r functions , e.g. , rabie s viru s [18] . Mithramycin i s a relate d compoun d tha t inhibit s influenz a an d pseudorabies viruse s probabl y du e t o inhibitio n o f hos t cel l RN A polymerase II [18] .

Cordyceptin (313 ) i s a fermentation produc t o f th e fung i Aspergillus nidulans and Cordyceps militaris. Cordyceptin inhibit s the synthesis of mRNA an d hence the replication o f both RNA an d DNA viruses [18] . [18] .

Toyocamycin (314 ) i s anothe r adenosin e derivativ e produce d b y Streptomyces toyocaensis [18] . This compoun d selectivel y inhibit s th e ribosomal RN A synthesi s i n fibroblasts . Th e synthesi s o f adenovirusspecific mRN A is also inhibited by 314 [18] .

Sinefungin i s a n adenin e derivative , isolate d fro m Streptomyces griseolus an d i t effectivel y inhibit s V V mRN A (guanine-7 -Jmethyltransferase an d hence inhibits methylation of its mRN A [18] . bilayer structure . Filipin show s activity agains t VSV and to less degree against influenza and Rauscher leukemia virions [18] . Amphotericin B is another related antifungal antibiotic. Its methyl ester is active against HSV-1 and -2, VV, SV and VSV with less cytotoxicity and improved water solubility [18] .

Aphidicolin i s a tetracycli c diterpenoid , produce d b y th e fungu s Cephalosporium aphilicola. It has the ability to inhibit HSV-1, -2, VV and herpetic keratitis of rabbit [19] . The mechanism of this compound is not yet established.

Cytochalasin B (316 ) i s a metabolite o f the mol d Helminthosporium dermatoideum [19] . It inhibits hexose transport i n cells and hence i t is used fo r th e stud y o f virus-specifi c glycoprotei n synthesis . I t show s potent inhibitor y activit y agains t HSV-1 an d -2 apparentl y du e t o th e inhibition of viral glycosylation [19] . Cytochalasin D is a closely related compound tha t show s activit y agains t adenoviru s bu t i t enhance s th e infectivity of poliovirus and parainfluenza [19] .

It is a phenolic acid, isolated from a Penicillium sp. and shows inhibitory activity against HSV-1 and -2, VV, Semliki forest, influenza A viruses and coxsackievirus. Its effect i s probably due to cytotoxicity [19] .

Additional antivira l microbial-derived metabolite s are summarized i n Table 13 . 

There i s a n urgen t nee d t o identif y nove l activ e chemotype s a s lea d fo r effective antivira l chemotherapy . Recen t year s hav e witnesse d grea t advances in this area. The enormity of natural products as antiviral agent s started t o b e expresse d i n th e are a o f antivira l chemotherapy . Thi s i s represented b y the FDA's approva l fo r clinica l investigatio n o f two plantderived compounds, in addition to one compound of marine origin and one microbial-derived compound . Ou t o f te n syntheti c approve d drug s between 1983-1994 , seve n wer e modeled o n a natural produc t pare n [4] .

The developmen t o f recen t technique s t o dereplicate , accuratel y detect , isolate, structurall y defin e an d automate d assa y th e bioactiv e natura l products will result in more lead of antiviral agents. It has been estimate d that onl y 5-15 % o f th e approximatel y 250 , 00 0 specie s o f highe r plant s have bee n systematicall y investigate d fo r th e presenc e o f bioactiv e compounds while the potential of the marine environment has barely bee n tapped [4] . Consequently , natura l product s represen t potentia l antivira l leading resources for imaginative discoverers. 

Natural Product s a s a Resource fo r New Drugs

Recent Natural Products Based Drug Development: A Pharamaceutical Industry Perspective

Plant Products as Potential Antiviral Agents

Natural Products in Drug Discovery and Development

The Virus A History of the Concept

Virology

Apoptosis i n Viral Infections. I n

Apoptosis: The Molecular Basis of Cell Death

Marburg an d Ebol a Viruses . I n

Antivira l Compound s fro m Plants

Plan t Substance s a s Antiviral Agents

Basi c & Clinica l Pharmacology

Antiviral Agents : Characteristic Activit y Spectru m Dependin g o n the Molecula r Targe t Wit h Whic h The y Interact

Interferon-Induce d Antivira l Action s an d Thei r Regulation. I n

Va n Hoof , L . Plan t Substance s a s Antiviral Agents

Biorgani c Marin e Chemistry

Antivira l Agent s fro m Natura l Sources

Chemotherapy o f Viral Infection . Natura l Products

Natura l Product s a s Antivira l Agents

Anti-Huma n Immunodeficienc y Virus (Anti-HIV ) Natura l Product s wit h Specia l Emphasi s o n HI V Revers e Transcriptase Inhibitors

Antivira l Substances

Screening o f Highe r Plant s fo r

Plant Antivira l Agents . III. Isolation o f Alkaloid s from Clivia miniata Rege l (Amaryllidaceae)

Antiherpe s Viru s Activit y o f Aporphine Alkaloids

Biologica l an d Phytochemical Evaluatio n o f Plants . V . Isolatio n o f Tw o Cytotoxi c Alkaloid s from Chelidonium majus

Effect o f Benzo[c]phenanthidin e Alkaloids on Reverse Transcriptase and Their Binding Property to Nucleic Acids

Evaluatio n o f Natura l Product s a s Inhibitors o f Huma n Immunodeficienc y Viru s Type-1 (HIV-1 ) Revers e Transcriptase

Anti-HI V an d Cytotoxic Alkaloid s fro m Buchenavia capitata

Antivira l Component s of Ophiorrhiza mungo

Tetrahydroxyoctahydroindolizidine Alkaloid , fro m Seed s o f Castanospermum Anstrale

Castanospermin e i n Alexia species

Inhibitio n o f Mammalian Digestiv e Disaccharide s b y Polyhydrox y Alkaloids

Anti-HI V Michellamine s fro m Ancistrocladus korupensis

Michellamin e B , A Novel Plan t Alkaloid, Inhibit s Huma n Immunodeficienc y Virus-Induce d Cel l Killin g b y a t Least Two Distinct Mechanisms

A n Activ e Antiviral Alkaloi d fro m Boehmeria cylinderica (L. ) SW . (Urticaceae)

a-Homono-jirimycin [2,6-Dideoxy-2,6-imino-Dglycerol-L-heptitol ] fro m Omphalea diandra L. : Isolatio n an d Glucosidas e Inhibition

Enzym e Inhibition . VIII : Mod e o f Inhibitio n o f Revers e TranscriptaseActivity b y Analogues, Isomers and Related Alkaloids o f Coralyne

Inhibitor y Natural Products . 26 . Quinolin e Alkaloid s fro m Euodia oxburghiana

Antiherpes viru s Actio n o f Atropine

Activit y i n Vitro of MGN-3, an Activated Arabinoxyla n from Ric e Bran

Myeloblastosi s an d Huma n Immunodeficiency Viru s Revers e Transcriptas e Inhibitors , Sulfate d Polysaccharides Extracte d fro m Se a Algae Antimicrob

Glycoprotein of Human Immunodeficiency Typ e 1 Bind s Sulfated Polysaccharide s and CD4-Derived Syntheti c Peptides

Reverse Transcriptas e Isolate d fro m Th e Malaysia n Tree , Callophyllum inophyllum Linn

E. a-(l-3)-D-Mannose-Specifi c Plan t Lectins Are Markedly Inhibitor y to Human Immunodeficiency Viru s an d Cytomegaloviru s Infection s In Vitro

Anti-Huma n Immunodeficiency Viru s Phenolic s from Licorice

The Calanolides , A Novel HIV-Inhibitor y Clas s o f Coumari n Derivative s fro m The Tropical Rainfores t Tre e Callophyllum langigerum

Specifi c Inhibitio n o f Th e Revers e Transcriptas e o f Huma n Immunodeficiency Viru s Typ e 1 an d Th e Chimeri c Enzyme s o f Huma n Immunodeficiency Viru s Typ e 1 an d 2 b y Non -nucleosid e Inhibitors

Specifi c Inhibition o f Huma n Immunodeficienc y Viru s Typ e 1 Reverse Transcriptas e Mediated by Soulattrolide, A Coumarin Isolate d from The Latex of Calophyllum teysmannii

Studie s of the Plantaginis herba. 9. Inhibitory Effects o f Flavonoids from Plantago Specie s on HIV Reverese Transcriptase Activity

Thre e Dimensiona l Quantitativ e Structure-Activit y Relationshi p (QSAR) o f HI V Integras e Inhibitors : A Comparativ e Molecula r Fiel d Analysi s

Activit y o f Som e Flavonoids Agains t Viruses

Antivira l Activit y o f Flavone s an d Flavans

Antiviral Activit y o f 3-Methoxyflavones , I n "Plan t Flavonoid s i n Biolog y an d Medicine: Biochemical , Pharmacologica l an d Structure-Activit y Relationships " Cody

Ne w Antivira l Compound s I n "Advances i n Viru s Research

Antivira l Avtivit y o f 5,6,7-. Chemother, Trimethoxyflavon e an d Its Potentiation o f the Antiherpes Activit y o f Acyclovir

Differentia l Inhibitory Effect s o f Variou s Her b Extract s o n Th e Activitie s o f Revers e Transcriptase an d Variou s Deoxyribonuclei c Aci d (DNA ) Polymerase

Isolation an d Structur e o f Woodorien , A Ne w Glucosid e Havin g Antivira l Activity fro m Woodwardia orientalis

Mechanisti c Evaluatio n o f Ne w Plant-Derive d Compounds Tha t Inhibi t HIV -Revers e Transcriptase

Biologica l Activitie s o f Lignans

Secondar y Metabolite s fro m Plant s a s Antiretroviral Agents : Promisin g Lead Structure s fo r Anti-HI V Drug s o f Th e Future

A n Investigatio n o f Th e Antivira l Activit y o f Podophyllum peltatum

Studie s o n Th e Pharmacologica l Activitiesof Amazonian Euphorbaceae

Assesmen t o f Th e Anti-HI V Activit y o f a Pin e Cone Isolate

Nove l I n Vitr o Anti-HI V Activ e Agents

Arctigeni n a s A Lea d Structur e fo r Inhibitor s o f Huma n Immunodeficiency Viru s Type-1 Integrase

Tw o Ne w Lignan s with Activit y Agains t Infuenz a Viru s fro m th e Medicina l Plan t Rhinacanthus nasutus

New Anti-HIV , Antimalarial an d Antifungal Compound s from Terminalia bellerica

Antivira l activit y o f Lignan s an d Their Glycosides from Justiciaprocumbens

Selective Inhibition o f Human Immunodeficienc y Virus Type-1

Synthesis and Anti-HIV Activit y o f l,r-Dideoxy-gossypo l and Related Compounds

Vergleic h De r Antivirale n Aktivita t Vo n Oxidierte r Kaffiisaure un d Hydrokaffeesaure Gege n Herpesvirus Hominis Typ I und typ 2 In Vitro

Antiviral Caffeoy l Ester s fro m Spondias mombin

Anti-AID S Agents , 1 . Isolatio n an d Characterization o f Fou r New Tetragalloylquini c Acid s a s A New Clas s o f HI V Reverse Transcriptas e Inhibitor s fro m Tanni c Acid

Anti -AIDS Agents, 2. Inhibitory Effect s o f Tannins on HIV Reverse Transcriptase an d HIV Replication i n H9 Lymphocyte Cells

Th e Peltatols , Nove l HIV-Inhibitor y Catecho l Derivative s from Pothomorphe peltata

Nove l Phloroglucinol s fro m Th e Plan t Melicope sessiliflora (Rutaceae)

Cytotoxi c an d Antiherpetic Activit y o f Phloroglucino l Derivative s fro m Mallotus japonicus (Euphorbiaceae)

Structur e o f Euglobal-Gl , -G 2 an d -G 3 fro m Eucalyptus gerandis. Thre e New Inhibitor s of Epstein-Barr Virus Activation

Structur e o f Syzygiol : A Skin-Tumo r Promotio n Inhibitor

HIV-Revers e Transcriptas e Inhibitor s o f Eucalyptus globulus

HIV-Inhibitor y an d Cytotoxic Oligostilbenes fro m th e Leaves of Hopea malibato

Inactivation o f Envelope d Viruse s b y Anthraquinone s Extracte d fro m Plants

Anthraquinone s a s A New Clas s o f Antivira l Agents Agains t Huma n Immunodeficienc y Virus

Light-Induce d Acidificatio n b y The Antiviral Agen t Hypericin

A Poten t Nove l HIV-Inhibitor y Naphthoquinon e Trime r from a Concospermum sp

Antivira l Phenylpropanoi d Glycoside s from th e Medicinal Plan t Markhamia lutea

Secondar y Metabolite s from Plant s a s Antiretroviral Agents : Promisin g Lead Structure for Anti-HlV Drugs of The Future

Purification an d Characterization o f Antiviral Substance s from Th e Bud of Syzygium aromatica

Antiviral Substance s from The Root of Paeonia species

EUagitannin s a s Activ e Constituent s o f Medicinal Plants

Structure an d Antiherpetic Activit y Amon g Th e Tannins

Antiviral EUagitannin s fro m Spondias mombin Phytochemistry

Inhibitor y Effect s o f Tannin s o n Revers e Transcriptas e fro m RN A Tumo r Virus

Anti-HIV Activit y o f EUagitannins

Comparativ e Studies of The Inhibitory Propertie s of Antibiotics o n Human Immunodeficienc y Virus and Avaian Myeloblastosi s Virus Reverse Transcriptas e an d Cellular DN A Polymerase

Viru s Inhibitio n b y Tea , Caffein e an d Tanni c Acid

Plant Antivira l Agents . VII. Antiviral an d Antibacterial Proanthocyanidin s fro m The Bark of Pavetta owariensis

A-Typ e Proanthocyanidin s fro m Ste m Bar k o f Pavetta owariensis

Dimeri c an d Trimeri c Proanthocyanidin s Possessin g A Doubl y Linke d Structur e fro m Pavetta owariensis

Antivira l Activit y o f Tanni n fro m Th e Pericarp of Punica granatum L . Against Genital Herpes Virus In Vitro

Effects o f Condensed Tannin s and Related Compounds on Reverse Transcriptase

Inhibitory Effects o f Tannic Acid Sulfate an d Related Sulfate s o n Infectivity, Cytopathi c Effec t an d Gian t Cel l Formatio n o f Huma n Immunodeficiency Vms

In Vitro Antiviral Activity o f Calcium Elenolate

Antivira l Agents o f Plant Origin . II . Antiviral Activit y o f Scopaduli c Aci d B Derivatives

Th e Effec t o f A^-Tetrahydrocannabino l o n Hepes simplex Viru s Replication

Antiviral Agent s o f Plant Origin . III . Scopadulin , A Nove l Tetracycli c Diterpen e fro m Scoparia dulcis

Inactivation o f Measel s Viru s an d Herpes simplex Viru s b y Saiko-saponins

Structur e o f Tw o Antivira l Triterpen e Saponin s fro m Anagallis arvensis

In Vitro Activity of Dammar Resi n Triterpenoid

Effect o f Saponins from Anagallis arvensis on Experimenta l Herpes simplex Keratiti s i n Rabbits

Preliminar y Studie s o f Antivira l Activit y o f Triterpenoi d Saponins : Relationships Betwee n Thei r Chemical Structure s an d Antiviral Activity

Antivira l Activitie s o f Glycerrhizin an d it s Modifie d Compound s Agains t Huma n Immunodeficienc y Virus Typ e 1 (HIV-1) an d Herpes simplex typ e 1 (HSV-1) In Vitro

Cytotoxi c Saponin s fro m Ne w Zealan d Myrsine Specie s

Triterpenoi d Saponin s fro m Maesa lanceolata

Triterpenoid Saponin s a s Anti-HI V Principle s from Fruit s o f Gleditsia japonica an d Gymnocladus chinensis an d A Structur e Activit y Correlation

Anti-HI V Triterpen e Acid s from Geum Japonicum

Betulinic Aci d an d Platani c Aci d a s Anti-HI V Principle s from Syzigum claviflorum an d The Anti-HIV Activit y o f Structurall y Relate d Triterpenoids

Betulini c Aci d Derivatives : A Ne w Class of Human Immunodeficienc y Viru s Type 1 Specific Inhibitor s with a New Mode of Action

Betulinic Aci d Derivatives : A Ne w Clas s o f Specifi c Inhibitor s o f Huma n Immunodeficiency Viru s Type 1 Entry

Antivira l Activit y o f Dammarane Saponin s Agains t Herpes Simplex Viru s I

Anti-AIDS Agents. 30. Anti-HIV Activit y o f Oleanoli c Acid, Pomoli c Aci d an d Structurall y Relate d Triterpenoids

Nigranoi c Acid , a Triterpenoid fro m Schisandra sphaerandra Tha t Inhibit s HIV-1 Revers e Transcriptase

Alkylidene Bicyclic Butenolide with Antiviral Activity and Its p-Glucopyranosid e from Homalium cochinchinensis

Molecular Similarit y o f Anti-HI V Phospholipids

Bryodi n 2 a Ribosome-Inactivatin g Protein fro m th e Plan t Bryonia dioica, 1990 , US patent

A n Antivira l Protei n from Bougainvillea spectabilis Roots ; Purificatio n an d Characterization

Protei n Toxin s an d Thei r Us e i n Cel l Biology

Expression Characteristic s o f Pokeweed Antivira l Proteins (PAPs) : Two Distinct Type s of Proteins

Action s o f Pokewee d Antiviral Protei n o n Virus-Infecte d Protoplasts

Plan t Immunomo-dulator s fo r Terminatio n o f Unwante d Pregnanc y an d fo r Contraception an d Reproductive Health

Inhibitio n o f Foo t an d Mout h Viru s (FMDV) Uncoating by a Plant-Derived Peptid e Isolate d from Melia azedarach L . Leaves. Argent

Th e Therapeuti c Potentia l o f Cationic Peptides

Nee m See d Oi l Inhibit s Aphi d Transmission o f Potat o viru s Y t o Pepper

Antiinfectiv e Activit y o f a Plan t Preparatio n from Geranium sanguineum L

In Vitro Anti-influenz a Viru s Activit y o f a plan t preparation fro m Geranium sanguineum L

Phyllanthus amarus Suppresse s Hepatiti s B Viru s b y Interruptin g Interactio n Betwee n HB V Enhance r I an d Cellula r Transcription Factors

Th e Plant s of Th e Genu s Phyllanthus a s a Potentia l Sourc e o f New Drugs

A Revie w of Th e Plant s o f Th e Genu s Phyllanthus: Thei r Chemistry , Pharmacolog y an d Therapeutic Potential

Nontoxi c Therapeuti c Extract s o f Larrea tridentata

In Vitro Activity o f Extracts of Persea americana Leave s on Acyclovir-Resistan t an d Phosphonoaceti c Resistan t Herpes simplex Virus

Antiviral Activit y o f a n Extrac t fro m Leave s o f th e Tropica l Plan t Acanthospermum hispidum

Interaction b y Various Plant Extracts

Anti-herpeti c Activit y o f Variou s Medicina l Plan t Extracts

Stud y o f Stapelia Pregnane s an d Veratrum Alkaloids

Anti-HI V Activit y o f Alkalin e Extract s o f Rooibo s Te a Leaves

Progres s i n Th e Acquisitio n o f Ne w Marine -Derived Anticance r Compounds : Developmen t o f Ecteinascidin-74 3 (ET-743)

Pharmacologicall y Activ e Compound s fro m Marin e Invertebrates: Drugs from the Sea

Marin e Product s a s a Sourc e o f Antivira l Dru g Leads . Drug Development Research

Antiviral an d Antitumor Compound s fro m Tunicates

Structure s of Th e Didemnins , Antivira l an d Antitumo r Depsipeptide s fro m a Caribbea n Tunicate

Antivira l an d Antitumo r Compound s fro m a Caribbea n Tunicate

Bioactiv e Peptides from a Marine Mollus k Elysia rufescens an d Its Algal Diet Bryopsis sp

Callipeltin A , an Anti-HIV Cycli c Depsipeptid e from th e New Caledonia n Lithistid a Spong e Callipelta sp

Eudistomin s C ; E ; K an d L ; Poten t Antivira l Compound s Containing Nove l Oxathiazepin e Rin g fro m Caribbea n Tunicat e Eudistoma olivaceum

Bromotopsenti n an d Dihydroxybromotopsentin: Antivira l and Antitumor Bis(Indolyl) Imidazoles from Caribbean Deep-Se a Sponge s o f th e famil y Halichon

d fro m a sponge Dercitus sp

A Ne w Guanidinostyren e fro m th e Cora l Tubastrea aurea

Nove l Antivira l an d Antimicrobia l Compounds from th e Spong e Acarnus erithacus (D e Laubenfles)

Revised Structure s of Polyandrocarpidines

Antivira l an d Antibacteria l Bromopyrrol s from Agelas coniferin and Hal o Derivative s Thereof

Bioactiv e Compounds from Aquati c an d Terrestria l Sources

Mycalamid e A , A n Antiviral Compoun d from a New Zealan d Spong e o f th e Genu s Mycale

Antivira l an d Antitumor Agent s from a Ne w Zealan d Sponge , Mycale sp . 2 . Structure s an d Solution Conformation s o f Mycalamides A and B

Isolatio n an d Structur e Elucidation of Onnamide A, a New Metabolite of a Marine Sponge, Theonella sp

Ptilomycalin A : A Novel Polycyclic Guanidine Alkaloid o f Marine Origin

New Antiviral an d Cytotoxic Compound s fro m th e Spong e Cramb e crambe

Bioactiv e Bisoxazole s from a Marine Sponge

Antiviral Indolocarbazole s from a Blue-Green Alg a Belongin g t o th e Nostocaceae

Aplidiasphingosine , a n Antimicrobia l an d Antitumo r Terpenoid from a n Aplidiiim sp . (Marine Tunicate)

Nove l Alkaloid s fro m th e Spong e Batzella sp. : Inhibitors o f HIV gpl20-Human CD 4 Binding

b-Carboline s fro m th e Blue-Gree n Alga Dichothrix baueriana

Alkaloid s fro m Antarcti c Spong e Kirkpatrickia varialosa. Par t 1 : Variolin B , a New Antitumo r an d Antivira l Compound

Unusua l Re d Pigmen t fro m Th e Spong e Trikentrion loeve, Anti-HIV-1 Metabolite

Contributio n t o Th e Stud y o f Marin e Products . XXXII. The Nucleosides o f Sponges

Antivira l Agent s from a Gorgonian

A Proto n Nuclea r Magnetic Resonance Study of The Antihypertensive and Antiviral Protein BDS-1 from Th e Se a Anemon e Anemonia sulcata: Sequentia l an d Stereospecifi c Resonance Assignmen t and Secondary Structure

2-(l-Chloro-2-hydroxyethyl)-4,4-Dimethylcyclohexa-2,5-dienone : A Precursor of 4,5-Dimethylbenzo[i]furan from The Red Alga Desmia hornemanni

Inhibitio n o f the Replicatio n of Etiologi c Agen t o f Acquire d Immun e Deficienc y Syndrom e (Huma n T -Lymphotropic Retroviru s /Lymphadenopathy-Associate d Virus ) b y Avaro l an d Avarone

Antivira l Chamigren e Derivative , PC T Internationa l Application W O 8 6 03

Sesquiterpenoid Isocyanid e Purificatio n from a Marine Sponge an d Its Use As a Neoplasm Inhibitor , Virucide and Fungicide

A n Antivira l Sesquiterpen e Hydroquinone from The Marine Sponge Strongylophora hartmani

Thre e New Sesquiterpen e Hydroquin-ones from Marine Origin

Frondosin s A an d D , HIV -Inhibitory Sesquiterpen e Hydroquinon e Derivative s from Euryspongia sp

Cytotoxic and Antiviral Diterpene from a Caribbean Deep Water Marine Sponge, Spongia sp

Ne w Antiinflammator y an d Antiviral Diterpenoid s fro m a Marine Octocoral o f The Genus Solenopodium

Brianthei n V , a New Cytotoxic an d Antiviral Diterpen e Isolate d from Briareum asbestinum

Reiswigin s A an d B , Nove l Antiviral Diterpene s fro m a Dee p Wate r Sponge

Bioactive Norsesterterpene 1,2-Dioxane s froma Thia Sponge , Mycale sp

Variabilin an d Relate d Compounds from a Sponge genus Sarcotragus

Venustatriol : A Ne w Antiviral Triterpene Tetracycli c Ether from Laurencia venusta

Holothurinosides : Ne w Antitumo r No n Sulphated Triterpenoi d Glycoside s from The Sea Cucumber Holothuriaforskalii

Biologically Activ e Saponin s an d Saponin-Lik e Compound s fro m Starfis h an d Brittle-Stars

New Secosteroids from an Undescribed Gorgonia n o f The Genu s Muricella

HIV-Inhibitor y Natura l Products . 11 . Comparative Studie s of Sulfated Sterol s from Marine Invertebrates

Weinbersterol Disulfate s A and B , Antivira l Steroi d Sulfate s fro m Th e Spong e Petrosia weinbergi

New Antivira l Stero l Disulfat e Ortho Esters fro m Th e Marin e Spong e Petrosia weinbergi

Meroterpene s fro m Cystoseira usneoides II

Cucumaria-xanthin s A , B and C from The Se a Cucumber Cucumaria Japonica

Caracterisation Chimiqu e e t Activit e Virostatiqu e in Vitro Vis d u Viru s d e la Fevere Jaune Quelques Carraghenanes Extrait s D'algues Roug e Senegalaises

Polysaccharides a s Antivira l Agents : Antiviral Activit y o f Carrageenan

Antivira l Carbohydrate s from Marin e Re d Algae

Antiviral and Anticoagulant Activity of Polysaccharides from marine brown algae

Antivira l Activitie s o f Sulfate d Derivative s o f a Fucosamine -Containing Polysaccharide o f Marine Bacterial Origin

Inhibitor y Effec t o f Sulfate d Derivative

Protectio n o f Tobacc o Plant s Against Tobacc o Mosai c Viru s b y b-l,3;l,6-Gluca n "Antivir " Obtaine d b y Enzymatic Transformatio n o f Laminarin

In Vitro Antiviral Activitie s o f Sulfated Polysaccharide s fro m a Marine Microalga {Cochlodinium polykrikoides) Against Huma n Immunodeficienc y Viru s an d Othe r Envelope d Viruses

a Sulfate d Mannose Polysaccharid e wit h Anti-HI V Activit y fro m Th e Pacifi c Tunicat e Didemnum molle

Brominate d Polyacetyleni c Avid s fro m Th e Marin e Spong e Xestospongia muta: Inhibitor s of HIV Protease

Petrosynol an d Petrosoli c Acid, Tw o Nove l Natura l Inhibitor s o f Th e Revers e Transcriptas e o f Huma n Immunodeficiency Viru s from Petrosia sp

Absolute Stereo -chemistr y o f Onchitriol s I and II

Mod e o f Inhibitio n o f HI V Revers e Transcriptase b y 2-Hexaprenylhydroquinone, a Novel Genera l Inhibito r of RNAand DNA-Directed DNA Polymerases

Antibioti c an d Antitumo r Misakinolid e Composition an d Thei r Derivatives . PC T Internationa l Applicatio n W O 8 8 00

A Ne w Inhibito r o f Huma n Cytomegaloviru s Proteas e fro m Streptomyces sp

A Nove l Antivira l Agents Whic h Inhibit s Th e Endouncleas e o f Influenz a Viruses

Sattabacin s an d Sattazolins : New Biologicall y Activ e Compound s with Antivira l Propertie s Extracte d from a Bacillus sp

Ne w Antivira l Antibiotics , Kistamicin s A an d B . I . Taxonomy , Production, Isolation , Physico -Chemica l Propertie s an d Biological Activities

Isolatio n an d Synthesi s o f Caprolactin s A and B , Ne w Caprolactam s from a Marin e Bacterium

Structures o f Ne w Polyacetylen e Triglyceride s an d Indolocarbazole s fro m Th e Myxomycetes Lycogala epidendrum

Antibiotic s fro m Glidin g Bacteri a XLVII. Thiangazole : A Novel Inhibito r o f HIV-1 fro m Polyangium sp

Fluvirucin s Al , A2 , Bl , B2 , B3 , B 4 an d B5 , Ne w Antibiotics Activ e Agains t Influenz a A Virus. I. Production, Isolation , Chemica l Properties an d Biological Activities

Structura l Studie s o f MM46115 , A Nove l Tetroni c Acid Containin g Macrolid e wit h Antivira l an d Antibacteria l Activit y Isolate d from Actinomadur a pelletieri

Antibiotic s fro m Glidin g Bacteria . XLIII . Phenoxan : A Nove l Inhibitor o f HIV-1 Infectio n i n Cel l Culture s from Polygoniu m sp. , Strai n P I V019 (Myxobacteria)

Structur e an d Biologica l Activity

A New Peptid e Antibiotic . Production, Isolation , an d Propertie s o f Lanthiopeptin

Manufactur e o f Diaminobutyri c Aci d Homopolymer wit h Streptoalloteichu s fo r Us e a s Antibioti c an d Virucide

Derivatives of Oxetanocin: Oxetanocins H, X and G and 2-Aminooxetanocin A

A Ne w Adenosin e Deaminase Inhibitor Containing Chlorine. Production, Isolation and Properties

A Novel Specific Inhibito r Against Reverse Transcriptase

Structur e o f Virantmycin , A Nove l Antivira l Antibiotic

Studie s o n SF-1836 C Substance . Meiji Seika Kenkyu Nempo

A New Antiherpetic Agent, AH-1763 lia, Produced by Streptomyces cyaneus Strai n No. 1763

Structur e o f Sc h 68631 : A New Hepatiti s C Virus Proteinas e Inhibito r fro m Streptomyces sp

Pradimici n Antibiotics an d Thei r Manufactur e wit h Actinomadura

New Antivira l Antibiotics , Cycloviracins B l an d B2.1. Production, Isolation , Physico-Chemica l Propertie s an d Biologica l Activities

The Structure s o f Quartromicin s Al , A 2 an d A3 : Novel Macrocycli c Antivira l Antibiotics Possessin g Fou r Tetroni c Aci d Moieties

Antibiotic s from Basidiomycetes . XXXIX. Podoscyphic Acid , A New Inhibito r of Avian Myeloblastosi s Viru s an d Moloney Murin e Leukemi a Viru s Revers e Transcriptas e fro m a Podoscypha Species