Inhibition of Hepatitis C Virus 3a genotype entry through Glanthus Nivalis Agglutinin

Division of Molecular Medicine, Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
Virology Journal (Impact Factor: 2.18). 05/2011; 8(1):248. DOI: 10.1186/1743-422X-8-248
Source: PubMed


Hepatitis C Virus (HCV) has two envelop proteins E1 and E2 which is highly glycosylated and play an important role in cell entry. Inhibition of virus at entry step is an important target to find antiviral drugs against HCV. Glanthus Nivalis Agglutinin (GNA) is a mannose binding lectin which has tendency for specific recognition and reversible binding to the sugar moieties of a wide variety of glycoproteins of enveloped viruses.
In the present study, HCV pseudoparticles (HCVpp) for genotype 3a were produced to investigate the ability of GNA to block the HCV entry. The results demonstrated that GNA inhibit the infectivity of HCVpp and HCV infected serum in a dose-dependent manner and resulted in 50% reduction of virus at 1 ± 2 μg concentration. Molecular docking of GNA and HCV glycoproteins (E1 and E2) showed that GNA inhibit HCV entry by binding N-linked glycans.
These results demonstrated that targeting the HCV glycans is a new approach to develop antiviral drugs against HCV.

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Available from: Usman Ali Ashfaq
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    • "E1 acts as a fusigenic subunit of the HCV envelope and contains 4–5 N-linked glycans. As it is known that the interaction of the virion with various cell receptors results in HCV infection [10,11]. Therefore, it is important to target virus envelope proteins to stop viral entry. "
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    ABSTRACT: Background HCV infection is a major health problem causing acute and chronic hepatitis. HCV E1 protein is a transmembrane protein that is involved in viral attachment and therefore, can serve as an important target for vaccine development. Consequently, this study was designed to analyze the HCV E1 protein sequence isolated in Pakistan to find potential conserved epitopes/antigenic determinants. Results HCV E1 protein isolated in Pakistan was analyzed using various bio-informatics and immuno-informatics tools including sequence and structure tools. A total of four antigenic B cell epitopes, 5 MHC class I binding peptides and 5 MHC class II binding peptides were predicted. Best designed epitopes were subjected to conservation analyses with other countries. Conclusion The study was conducted to predict antigenic determinants/epitopes of HCV E1 protein of genotype 3a along with the 3D protein modeling. The study revealed potential B-cell and T-cell epitopes that can raise the desired immune response against HCV E1 protein isolated in Pakistan. Conservation analysis can be helpful in developing effective vaccines against HCV and thus limiting threats of HCV infection in Pakistan.
    Full-text · Article · Apr 2013 · Virology Journal
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    • "Each of these steps, although not completely defined, is likely mediated by the HCV E1 and/or E2 envelope glycoproteins. In vitro, proof-of-concept for inhibiting the HCV entry process has been demonstrated using Glanthus nivalis Agglutinin (GNA) that targets the N-linked glycans of the viral envelope proteins and prevents E2-CD81 interaction [21], neutralizing antibodies directed against the HCV E1 and E2 proteins [22-27], antibodies against cellular receptors CD81 [9,11,28-31], SR-BI and agents that block endosomal acidification [32]. In this study, HCVpp of local HCV genotype 3a were produced to study early entry steps mediated by HCV envelope glycoproteins. "
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    ABSTRACT: HCV causes acute and chronic hepatitis which can eventually lead to permanent liver damage hepatocellular carcinoma and death. HCV glycoproteins play an important role in HCV entry by binding with CD81 receptors. Hence inhibition of virus at entry step is an important target to identify antiviral drugs against HCV. The present study elaborated the role of CD81 and HCV glycoprotein E2 in HCV entry using retroviral pseudo-particles of 3a local genotype. Our results demonstrated that HCV specific antibody E2 and host antibody CD81 showed dose- dependent inhibition of HCV entry. HCV E2 antibody showed 50% reduction at a concentration of 1.5 ± 1 μg while CD81 exhibited 50% reduction at a concentration of 0.8 ± 1 μg. In addition, data obtained with HCVpp were also confirmed with the infection of whole virus of HCV genotype 3a in liver cells. Our data suggest that HCV specific E2 and host CD81 antibodies reduce HCVpp entry and full length viral particle and combination of host and HCV specific antibodies showed synergistic effect in reducing the viral titer.
    Full-text · Article · Nov 2011 · Journal of Translational Medicine
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    ABSTRACT: Background HCV affects >170 million people worldwide and is a leading cause of liver diseases such as hepatocellular carcinoma. Each year, Pakistan reports hundreds of cases and now it has become a serious health issue. HCV has two transmembrane glycoproteins (E1 and E2) that are involved in virus entry through viral attachment, but because of their hypervariable nature they have become difficult targets for vaccine development. Methods A total of 150 protein sequences of E1 and E2 belonging to genotypes 3a and 1a were retrieved from the NCBI protein database and were subjected to conservation and variation analysis using the multiple sequence alignment feature of the CLC workbench. A consensus sequence of each genotype of E1 and E2 was obtained and these consensus sequences were further analyzed to construct a global consensus sequence, which was used to design potentially conserved peptides. Results From the sequence conservation analysis, highly conserved residues were identified and were used to design peptides. Only two peptides were found to be conserved in the E1 protein of genotypes 3a and 1a and a total of nine conserved peptides were designed for the HCV E2 protein of those genotypes. These designed peptides could serve as useful targets in developing new inhibitory compounds. Conclusion This study was designed to perform conservation and variability analysis of HCV glycoproteins and to find potentially conserved peptides among genotypes 3a and 1a (the most prevalent genotypes in Pakistan) that could serve as useful targets in the development of novel inhibitory compounds, thus reducing the threat of HCV infection in Pakistan.
    Full-text · Article · Apr 2013 · Theoretical Biology and Medical Modelling