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Three dimensional structure of broadly neutralizing anti - Hepatitis C virus (HCV) glycoprotein E2 alpaca nanobody D03
Structural highlights
Publication Abstract from PubMedSevere liver disease caused by chronic hepatitis C virus is the major indication for liver transplantation. Despite recent advances in antiviral therapy, drug toxicity and unwanted side-effects render effective treatment in liver-transplanted patients a challenging task. Virus-specific therapeutic antibodies are generally safe and well-tolerated, but their potential in preventing and treating HCV infection has not yet been realized due to a variety of issues, not least high production costs and virus variability. Heavy-chain antibodies (HCAbs) or nanobodies, produced by camelids, represent an exciting antiviral approach - they can target novel highly conserved epitopes that are inaccessible to normal antibodies and they are also easy to manipulate and produce. We isolated four distinct nanobodies from a phage-display library generated from an alpaca immunized with Hepatitis C virus E2 glycoprotein. One of them, nanobody D03, recognized a novel epitope overlapping with the epitopes of several broadly neutralizing human monoclonal antibodies. Its crystal structure revealed a long CDR3 folding over part of the framework that - in conventional antibodies - forms the interface between heavy and light chain. D03 neutralized a panel of retroviral particles pseudotyped with HCV glycoproteins from six genotypes and authentic cell-culture derived particles by interfering with E2-CD81 interaction. In contrast to some of the most broadly neutralizing human anti-E2 mAbs, D03 efficiently inhibited HCV cell-to-cell transmission. Conclusion:This is the first description of a potent and broadly neutralizing HCV-specific nanobody representing a significant advance that will lead to future development of novel entry inhibitors for the treatment and prevention of HCV infection and help our understanding of HCV cell-to-cell transmission. (HEPATOLOGY 2013.). An alpaca nanobody inhibits hepatitis C virus entry and cell-to-cell transmission.,Tarr AW, Lafaye P, Meredith L, Damier-Piolle L, Urbanowicz RA, Meola A, Jestin JL, Brown RJ, McKeating JA, Rey FA, Ball JK, Krey T Hepatology. 2013 Mar 28. doi: 10.1002/hep.26430. PMID:23553604[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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