Hemocyanins (Hcs) are oxygen-binding glycoproteins, freely dissolved in the hemolymph, of many arthropods and mollusks


ISJ 10: 120-127, 2013                                                       ISSN 1824-307X 
 
 

REVIEW 
 
Antiviral activity of hemocyanins
 
P Dolashka , W Voelter1 2
 
1Institute of Organic Chemistry with Centre of Phytochemistry, BAS, Sofia, Bulgaria
2Interfacultary Institute of Biochemistry, University of Tϋbingen, Hoppe-Seyler-Strasse 4, D-72076 Tϋbingen, 
Germany. 
 
 

   Accepted October 11, 2013 
 

Abstract 
Hemocyanins are giant biological macromolecules acting as oxygen-transporting glycoproteins. 

Most of them are respiratory proteins of arthropods and mollusks, but besides they also exhibit 
protecting effects against bacterial, fungal and viral invasions. As discovered by 2-DGE proteomics 
analyses, several proteins including hemocyanins of hemocytes from virus-infected arthropods 
increased upon infection, confirming hemocyanin’s role as part of the organism’s defence system. 
Based on the structural analyses of molluscan Hcs it is suggested that the carbohydrate chains of the 
glycoproteins seem to interact with surface-exposed amino acid or carbohydrate residues of the 
viruses through van der Waals interactions. 
 
Key Words: functional units; hemocyanin; mollusks; arthropods; viruses 
 
 
 
Introduction 

 
The persistence of the virus in the organism 

leads to the development of lymphoproliferative 
disease, the formation of various carcinomas and to 
the affection of the peripheral and central nervous 
system. Antiviral drugs may be divided into acyclic 
nucleoside analogues (aciclovir, ganciclovir, 
penciclovir), acyclic nucleotide analogues (cidofovir 
and adefovir), and substances of natural origin (De 
Clercq, 2004). Most of the submitted drugs are 
potent inhibitors of viral reproduction, but not all of 
them are promising for clinical application, since 
they are very different in terms of toxicity. 

Recently it was found that hemocyanins (Hcs), 
the oxygen-transporting glycoproteins of many 
arthropods and mollusks, could be also potential 
inhibitors of some virus infections (Chongsatja et al., 
2007; Flegel et al., 2011). These giant glycoproteins 
which differ in molecular mass, structure, 
carbohydrate content, and monosaccharide 
composition have recently received increasing 
interest due to their significant immunostimulatory, 
antitumor, and antiviral properties (Dolashka-
Angelova et al., 2009; Dolashka et al., 2010; Mičetić 
et al., 2010; De Smet et al., 2011; Rehm et al., 
2012; Markl et al., 2013). Both species, molluscan 
___________________________________________________________________________ 

 
Corresponding author: 
Pavlina Dolashka 
Institute of Organic Chemistry with Centre of 
Phytochemistry 
BAS, Sofia, Bulgaria
E-mail: pda54@abv.bg; dolashka@orgchm.bas.bg

 
 

and arthropodan Hcs, contain copper-containing 
active sites in which the Cu(I,I) is oxidized to the 
Cu(II,II) state, thus accounting for their distinctive 
deep blue color. The biosinthesis of hemocyanins 
from e.g. Concholepas concholepas (CcH) takes 
place in the hepatopancreas (Manubens et al., 
2010) but Megathura crenulata’s Hcs originate from 
rhogocytes (Martin et al., 2011). 

Investigations on several molluscan 
hemocyanins, e.g. from Haliotis tuberculata (HtH, 
Abalon) (Markl et al., 2001); Helix lucorum (HlH, 
garden snail), Rapana venosa (RvH, Black sea 
murex) (Dolashka-Angelova et al., 2003, 2009, 
2011; Iliev et al., 2008) or C. concholepas (CCH, 
Loco) from the Pacific Chilean coast (Moltedo et al., 
2006, Arancibia et al., 2012) demonstrated their 
remarkable immunostimulatory properties in 
experimental animal model and clinical studies. 
Moreover, hemocyanins have been extensively 
used as carriers to generate antibodies against 
diverse hapten molecules and peptides to induce 
antigen-specific CD8+ and CD4+ T cell responses 
(Minozzi et al., 2007; Arancibia et al., 2012). 
Recently, a vaccine potential of Oncomelania 
hupensis Hc against Schistosoma Japonicum 
parasite was also established (Guo et al., 2011). 

Probably, due to their high carbohydrate 
content and specific monosaccharide composition, 
Hcs were also found to be active against viruses 
(Dolashka-Angelova et al., 2009, 2010). Proteomic 
analysis of differentially-expressed proteins in 
arthropodan Penaeus vannamei hemocytes upon 

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Fig. 1 Pseudoatomic model of emperor scorpion hemocyanin used for molecular replacement (Jaenicke et al., 
2012).
 
 
 
 
Taura syndrome virus (TSV) infection showed 
increased expression of hemocyanin 
(Rattanarojpong et al., 2009). The efficacy, against 
white spot syndrome virus (WSSV) and Singapore 
grouper iridovirus (SGIV) is also assigned to a 
protein of the arthropod Penaeus monodon (Zhang 
et al., 2004). 

Antiviral properties of molluscan Hcs were 
reported for the first time discribing the inhibition 
effect of hemocyanins from gastropod R. venosa 
(RvH) against Respiratory syncytial virus (RSV) and 
Herpes simplex virus type-1, strain Vic (HSV-1) 
(Dolashka et al., 2010; Dolashka-Angelova et al., 
2011; Nesterova et al., 2011). As this property 
seems to be associated with the glycosylation of 
functional units, the oligosaccharide structures of R. 
venosa and related molluscan and arthropodan 
hemocyanins were determined using different 
analytical physycochemical thechniques, (Sandra et 
al., 2007; Dolashka-Angelova et al., 2009; Dolashka 
et al., 2010). 

In this short review, current knownledge about 
structural and biochemical aspects and eventual 
potential future clinical applications of arthropodan 
and molluscan hemocyanins as antiviral drugs is 
presented, and biochemical mechanisms causing 
the antiviral activity are suggested. 
 
Arthropodan hemocyanins 
 
Structure of arthropodan hemocyanins 

Hemocyanins evolved early in the arthropod 
stem lineage from phenoloxidases, O2

-consuming 
enzymes involved in the melanin pathway. They 

form hexamers or oligo-hexamers of identical or 
related subunits with a molecular mass of about 75 
kDa (Fig. 1) (Dolashka-Angelova et al., 2001; 
Mičetić et al., 2010; Jaenicke et al., 2012). Each 
subunit contains three domains and O2-binding is 
mediated by two Cu+ ions which are coordinated by 
six histidine residues ("type III” copper binding site). 
Subunit interactions within the multisubunit 
hemocyanin complex lead to diverse allosteric 
effects such as the highest cooperativity for oxygen 
binding found in nature. Based on biochemical, 
immunochemical and molecular phylogenetic 
analyses, distinct hemocyanin subunit types have 
been identified in chelicerata, myriapoda, crustacea 
and hexapoda (Huang et al., 2008; Rehm et al., 
2012). The crystal structure of a native hemocyanin 
oligomer larger than a hexameric substructure was 
published for the first time for the 24-meric 
hemocyanin (MW = 1.8 MDa) from emperor 
scorpion (Pandinus imperator) (Fig. 1) (Jaenicke et 
al., 2012). 
 
Antiviral activity of arthropodan hemocyanins 

Several reports on antiviral effects of 
arthropodan Hcs appeared in the literature, e.g. Hcs 
from shrimp Penaeus japonicus (PjH) and P. 
vannamei (PvH), against white spot syndrome virus 
(WSSV), Taura syndrome virus (TSV), yellow head 
virus (YHV) (Lei et al., 2008; Chongsatja et al., 
2007; Rattanarojpong et al., 2007; Nesterova et al., 
2011). Hcs-based antiviral therapies are also 
reported (Lin, 2005; Balzarini et al., 2007). 

One of these viruses, the white spot syndrome 
virus (WSSV) caused billions of dollars of losses for 

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Fig. 2 Quaternary structure of molluscan hemocyanins: a) side view of didecamer; b) top view of decamer; c) 
structural subunits and functional units; d) electron microscopic picture of the native molecule of molluscan 
hemocyanin (Lieb et al. 2008). 
 
 
 
 
 
shrimp farmers. To reduce shrimp production 
losses, stimulated since 2000 a plethora of research 
programmes to test shrimp’s responses against viral 
pathogens at the molecular level. Humoral 
responses, binding studies between shrimp and 
viral structural proteins including intracellular 
responses, viral persistence co-interactions as well 
as viral sequence determination of the shrimp 
genome were subject of these investigations. Based 
on these results, a novel practical method for 
improved disease control was developed (Flegel et 
al., 2011). 

Studies on shrimp P. japonicus (PjH) showed 
that its hemocyanin could delay the infection of 
white spot syndrome virus (WSSV) in vivo and its 
subunits have different behavior in anti-WSSV 
defense (Table 1). During WSSV infection a strong 
induced one also cloned subunits, PjHcL was 
observed in contrast to subunit Pj-HcY. These 
findings suggest a possible discrepancy between 
the two subunits in shrimp innate immunity (Lei et 
al., 2008). 

To understand the molecular responses of 
crustacean hemocytes to virus infection, a two-
dimensional electrophoresis (2-DE) proteomics 
approach was applied to determine altered proteins 

in hemocytes of P. vannamei during Taura 
syndrome virus (TSV) and yellow head virus (YHV) 
infections (Rattanarojpong et al., 2007; Chongsatja 
et al., 2007). 

Proteomic analysis of P. vannamei hemocytes 
(PvH) upon YHV and TSV infection show the 
differentially-expressed proteins from the 
hemocytes. In the proteomic analysis of gills from 
yellow head virus-infected P. vannamei, 13 spots 
with up-regulated protein expression levels and five 
spots with down-regulated levels were identified. 
LC-nano-ESI-MS/MS indicated that the up-regulated 
proteins included enzymes in the glycolytic pathway, 
the tricarboxylic acid cycle and amino acid 
metabolism. The other upregulated proteins were 
arginine kinase, imaginal disk growth factor (IDGF) 
and a Ras-like GTP protein. These results provide 
preliminary data, however, it was not able to assign 
specific YHV-response status to any of the up-
regulated or down-regulated genes identified after 
YHV challenge (Rattanarojpong et al., 2007). 

Proteomic analysis was also applied to explain 
the antiviral effect of P. vannamei hemocyanin 
(PvH) against Taura syndrome virus (TSV) 
(Chongsatja et al., 2007). At 24 h post infection of 
PvH with Taura syndrome virus (TSV), quantitative 

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Table 1 Antiviral activity of several molluscan and arthropodan hemocyanins against different viruses 
 

Hemocyanins Viruses Efficacy References 
Arthropodan Hcs 

P. japonicus (PjH), White spot syndrome virus (WSSV) - Lei et al., 2008 
PjHcY, PjHcL WSSV + Lei et al., 2008 
P. vannamei  (PvH), Taura syndrome virus (TSV) + Chongsatja et al., 2007 
PvH Yellow head virus (YHV) + Rattanarojpong et al., 2007 
P. monodon Singapore grouper iridovirus (SGIV)  Zhang et al. 2004 
    

Molluscan Hcs 
Rapana venosa    
RvH, RvH1 and RvH2 Polio virus type 1(LSc-2ab) - Dolashka-Angelova 2009 
RvH, RvH1 and RvH2 Respiratory syncytial virus (RSV) - Dolashka-Angelova 2009 
RvH, RvH1 and RvH2 Coxsackie virus B1 (CV-B1)  Dolashka-Angelova 2009 
Gglycosylated RvH-b RSV - Dolashka-Angelova 2009 
Nonglycosylated RvH-b RSV - Dolashka-Angelova 2009 
Gglycosylated RvH-c RSV + Dolashka-Angelova 2009 
Nonglycosylated RvH-c RSV - Dolashka-Angelova 2009 
RvH, RvH1 and RvH2 Epstein Barr virus - Velkova et al., 2009 
Helix vulgaris (HvH) Epstein Barr virus - Zagorodnya et al., 2011 
RvH, RvH1 and RvH2 HSV-1 - Nesterova et al., 2010 
Helix vulgaris (HvH) HSV-1 - Nesterova et al., 2010 
RvH2-e HSV-1 + Nesterova et al., 2010 

 
 
 
 
intensity analysis and nano-LC-ESI-MS/MS 
revealed 8 proteins that were significantly up-
regulated, whereas 5 proteins were significantly 
down-regulated in the infected shrimps. All of these 
proteins (hemocyanin, catalase, carboxylesterase, 
transglutaminase, and glutathione transferase) play 
important roles in host defense, signal transduction, 
carbohydrate metabolism, cellular structure and ER-
stress response. However, hemocyanin, is one of 
these up-regulated proteins indicating a relation 
between this protein and the organism’s defence 
system. 

To get more insight into the molecular 
mechanism of the immune response of P. vannamei 
during Taura syndrome virus (TSV) infection, 
expression and functional proteomics studies were 
performed on its hemocyanin, which is a major 
abundant protein in shrimp hemocytes. Two-
dimensional electrophoresis revealed up-regulation 
of several C-terminal fragments of hemocyanin, 
whereas the N-terminal fragments were down-
regulated during TSV infection. 2-D Western blot 
analysis showed that the C-terminal hemocyanin 
fragments had more acidic isoelectric points (pI), 
whereas the N-terminal fragments had less acidic 
pIs. By motif scanning an important motif was 
discovered in the C-terminal hemocyanin, the ERK 
D-domain, of required for activation of ERK1/2 
effector kinase, as a kinase-binding site at Val527 in 
the hemocyanins C-terminus, whereas no functional 
domain was found in the N-terminus. Co-
immunoprecipitation confirmed the interaction 
between the C-terminal hemocyanin and ERK1/2 
which was also up-regulated during TSV infection. 
These findings demonstrate for the first time that the 
ERK1/2 signaling pathway may play an important 
role in molecular immune response of P. vannamei 
upon TSV infection through its interaction with the 
C-terminal hemocyanin (Havanapan et al., 2009). 

Molluscan hemocyanins 
 
Structure of molluscan hemocyanins 

Molluscan hemocyanins (Hcs) are giant 
biological macromolecules acting as oxygen-
transporting glycoproteins. They have recently 
received particular interest due to their 
immunostimulatory and antitumoral properties. Most 
of them are glycoproteins with molecular mass 
around 9000 kDa organized as decamers or 
didecamers (Fig. 2) (Lieb et al. 2008; Markl, 2013). 
The native hemocyanins contain one or two 
structural subunits with molecular masses around 
350 - 450 kDa. Seven or eighth functional units with 
molecular masses of 50 kDa organize one structural 
subunits (Fig. 2) (Dolashka-Angelova et al., 2003a; 
Lieb et al. 2008; De Smet et al., 2011). 

Molluscan hemocyanins possess certain 
inhibitory properties against tumor cells and viruses 
(Iliev et al., 2008; Toshkova et al., 2009; Dolashka 
et al., 2011), as also found for the molluscan 
hemocyanins R. venosa (RvH) and H. lucorum (HlH) 
against different viruses (Dolashka-Angelova et al., 
2009, 2010; Nesterova et al., 2010 2011; 
Zagorodnya et al., 2011; Velkova et al., 2011). 
 
Antiviral activity of molluscan hemocyanins 

The antiviral effect of RvH and its isoforms was 
studied against polio virus type 1 (LSc-2ab), 
coxsackie virus B1 (CV-B1), respiratory syncytial 
virus (RSV) and Epstein Barr virus (EBV). After 
treatment of the viruses with the native RvH, the 
non-glycosylated and glycosylated functional units 
RvH-b and RvH-c, the quantitative virucidal 
suspension test did not show any effect against 
polio virus type 1 (LSc-2ab), coxsackie virus B1 
(CV-B1). Also no antiviral effects of native RvH 
against RSV was observed. However, the results 
presented in Table 1 show that only the glycosylated 

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Fig. 3 3D model of βcHlH-g created by using the Swiss PDB viewer and the model of functional unit “g” from 
Octopus dofleini (OdH-g) hemocyanin. Glycans and the putative glycosilated sites N125 and N245 are represent 
as balls (Kostadinova et al., 2013). 
 
 
 
 
 
FU, RvH-c, possesses some antiviral effect against 
the replication of RSV, at both viral doses tested 
(Dolashka-Angelova et al., 2009). In contrast, non-
glycosylated FU RvH-b does not reveal any antiviral 
activity against the replication of RSV, poliovirus 
type 1 (LSc-2ab) and CV-B1. This is the first report 
of the fact that molluscan hemocyanin functional 
units with specific glycosylation possess antiviral 
activity (Dolashka-Angelova et al., 2009). 

The properties of native hemocyanins from R. 
venosa and Helix vulgaris (HvH) snails and their 
structural subunits RvH1, RvH2, HvH1, and HvH2 
have been studied in vitro as substances with 
feasible antiEBV activity (Velkova et al., 2009). 
Epstein Barr virus (family Herpesveridae) is one of 
the etiologic agents that cause Burkitt's lymphoma 
and nasopharyngeal carcinoma, but drugs for 
antiEBV treatment are limited. There are few 
approaches for the treatment of this viral infection, 
namely, the use of effective antiviral chemotherapy, 
serotherapy or seroprevention which supposes the 
use of specific human immunoglobulins and 
vaccines (Pagano and Gershburg, 2005). The 
influence of R. venosa hemocyanin on viability and 
proliferative activity of lymphoblastoid cells was 

characterized by cytomorphological and colorimetric 
methods and an antiviral effect was observed after 
treatment with FUs RvH1-a and RvH2-e (Nesterova 
et al., 2010). 

Antiviral effects on R. venosa and H. vulgaris 
(HvH) hemocyanins, their structural subunits, the 
glycosylated functional unit RvH2-e and the non-
glycosylated unit RvH2-c were also investigated 
against HSV virus type 1: only the glycosylated FU 
RvH2-e exhibited an antiviral activity, which 
probably is due to its high carbohydrate content and 
specific monosaccharide composition (Zagorodnya 
et al., 2011; Velkova et al., 2011). 

Based on the obtained results, we suggested 
for the first time that the complete native RvH 
molecule lacks any antiviral activity because the 
carbohydrate chains are buried in between the 
structural subunits of the global protein and 
therefore, are unable to interact with the viral 
surface glycoproteins. To support this hypothesis, 
we found that two putative glycosylated sites in FUs 
βcHlH-g are exposed on the surface of the molecule 
(Fig. 3) (Kostadinova et al., 2013) and that FU 
RvH1-a, exhibits antiviral activity and bears two N-
glycosidic resirues attached to Asn262 and Asn401. 

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Fig. 4 3D model of functional unit RvH2-e. Amino acid residues included in the loops are shown in blue and green 
(Dolashka et al., 2010) 
 
 
 
 
 
Glycosylation of hemocyanins  

The relevance of specific glycosylation patterns 
as a differentiating factor for immunostimulatory 
properties has already been raised in studies on the 
hemocyanin isoforms KLH1 and KLH2 of M. 
crenulata and R. venosa, (Geyer et al., 2005; 
Sandra et. al., 2007). Molluscan hemocyanin genes 
contain several potential N-glycosylation sites, and 
some of those have been already effectively 
demonstrated to be glycosylated using a series of 
analytical strategies and MALDI-TOF-MS and 
tandem mass spectrometry (Lieb et al. 2008; 
Dolashka-Angelova et al., 2009; Dolashka et al., 
2010; De Smet et al., 2011). The identification of the 
oligosaccharide structure of several molluscan 
hemocyanins revealed a highly heterogeneous 
mixture of glycans of the compositions Hex0–9 
HexNAc2–4 Hex0–3 Pent0–3 Fuc0–3. A novel type 
of N-glycan with an internal fucose residue 
connecting one GalNAc(b1-2) and one hexuronic 
acid, was detected which also occurs in subunits 
RvH1 and RvH2 (Sandra et. al., 2007; Dolashka-
Angelova et al., 2009; Dolashka et al., 2010). 

Based on the obtained information about 
carbohydrate structure of hemocyanins the antiviral 

properties of hemocyanins against Herpes simplex 
virus type 1, was suggested. One potential site for 
N-glycosylation in FU RvH2-e at Asn-127 was 
shown to be glycosylated and this carbohydrate 
chain is likely to interact with specific regions of 
glycoproteins of HSV, through van der Waals 
interactions in general or with certain amino acid 
residues in particular. As is shown in figure 4 
several groups of these residues can be identified 
on the surface of RvH2-e which may interact with a 
carbohydrate chains of glycoprotein gp120 of HSV. 
The surface of glycoprotein gp120 was very well 
analysed (Sander et al., 2002). 

 
Development and identification of polyclonal 
antibodies against viruses 

Hemocyanins are commonly used to develop 
polyclonal antibodies e.g. also against predicted B 
cell epitopes in HIV-1 accessory protein Vpr. The 
synthesized B-cell peptide epitopes were 
subsequently conjugated with keyhole limpet 
hemocyanin (KLH) and then used to immunize 
rabbits. The antibody titers and specifities were 
determined by ELISA, Western-blotting, and 
immunoprecipitation analyses, respectively. Two B 

 125



cell epitopes of Vpr were successfully predicted by 
bio-informatical methods and polyclonal antibodies 
against those peptides could be successfully 
prepared (Sun et al., 2012). 

KLH was used to analyse the protective 
potential of polyclonal IgG antibodies specific to the 
ectodomain (eM2) of M2 protein of influenza A virus 
(IAV) against lethal influenza infection of mice. Two 
fractions, KLH alone and the ectodomain eM2, 
conjugated to KLH, were administered with Freund's 
adjuvant intraperitoneally (i.p.) to BALB/c mice. 
Analysis of the preparation of anti-KLH-eM2 IgGs by 
ELISA revealed that it contained about 25% of anti-
eM2 IgGs and 75% of anti-KLH IgGs and after 
infection with 3 LD50 IAV, a 100% survival of mice 
was observed with 320 µg anti-eM2IgGs (Király et 
al., 2011). 

Recently, molluscan hemocyanins receive 
increasing interest in vaccine development. 
Several carrier proteins were used to prepare 
vaccines against highly variable HIV-1. Two 
synthesized peptides, JY1 (V3 region of HIV-1 
gp120, subtype D) and JY1-MAP8, were coupled 
to carrier proteins such as KLH, hepatitis B surface 
antigen (HbsAg) and meningococcal P64k protein 
and used for immunization in mice. It was found 
that JY1-MAP8 conjugates were more 
immunogenic than JY1-MAP8 alone. Furthermore, 
conjugates to HBsAg and KLH were more 
immunogenic than those to P64k. The analysis 
showed that conjugate-based immunogens are 
more prompt to elicit immunogenicity and cross-
reactivity and hemocyanins are promising 
candidates the development of HIV vaccines (Cruz 
et al., 2009). 

We found that hemocyanins are a new class of 
natural antiviral compounds against different 
viruses. However, arthropodan hemocyanins are 
active against those own viruses of arthropods, 
such as WSSV and TSV, while the molluscan 
hemocyanins are active against viruses of human, 
such as RSV and EBV. Maybe the mechanisms of 
antiviral activity of both species are different and 
therefore, we consider them as an appropriate for 
further investigation as antiviral agents. 
 
 
Acknowledgement 

This work was supported by Deutsche 
Forschungsgemeinstchaft (DFG-STE 1819/5-
1/2012), Germany, Bulgarian Ministry of Education, 
projects TK01-496/2009, VU-L-310/2007,DAAD-
17/2007 and “Young researchers” DMU 03/26, grant 
№BG051PO001-3.3.06-0025, financed by the 
European Social Fund and Operational Programme 
Human Resources Development (2007 – 2013) and 
co-financed by Bulgarian Ministry of Education, 
Youth and Science and Fund for Scientific 
Research-Flanders (FWO-Vlaanderen, project 
VS.011.06N). 
 
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