Entry inhibitors

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Inhibitors of viral attachment

                The lectin cyanovirin-N (CV-N) has initially been discovered as an active compound against HIV and was then shown to present antiviral activity against other enveloped viruses (98, 99). This antiviral activity results from interactions between CV-N and high-mannose oligosaccharides on viral envelope glycoproteins (100). HCV envelope glycoproteins are highly glycosylated and contain oligomannose glycans. It has been shown that these oligomannose glycans interact with CV-N resulting in HCV antiviral activity by blocking HCV entry into target cell (101). As most of the HCV glycosylation sites are highly conserved, drugs that target glycans on HCV glycoproteins may not lead so rapidly viral escape/resistance as it is the case for HIV (92). Other carbohydrate-binding agents, such as plant lectins, monoclonal antibodies and the mannose-specific non-peptidic antibiotic Pradimicin A have been shown to prevent HIV infectivity (102). Such substances might also be efficient against other viruses that require a glycosylated envelope for entry into target cells.

                Another approach to target HCV attachment might be the development of heparin-derived molecules, as heparin has been shown to potently inhibit HCV E2, HCVpp, HCV-LP as well as HCVcc binding to hepatoma cells (32, 35, 53, 103). The systematic generation and screening of heparan sulfate-like molecules and semisynthetic derivatives is already explored as an antiviral approach against dengue virus infection (104).

Inhibitors of post binding steps

                Antiviral compounds targeting viral entry may either act on conserved mechanisms or target specific cell surface molecules. Recent studies have shown that long phosphorothioate oligonucleotides (PS-ON), that are amphipathic DNA polymers, displays a sequence independent antiviral activity against HIV by blocking virus-cell fusion (105). Most recently, it could be demonstrated that PS-ON inhibit HCV fusion and entry (Matsumara T, Kato K, Hu Z, Juteau JM, Vaillant A, Liang JT. The 57^th Annual Meeting of the American Association for the Study of Liver Diseases, 2006, Boston, USA). The PS-ON are a promising new class of antiviral compounds that may have a broad spectrum in all families of enveloped viruses.

                Structural information of HCV envelope glycoprotein E2 and CD81 was used to identify imidazole based compounds that mimic an alpha helix in the LEL of CD81 and compete for the binding of HCV E2 to CD81 expressed on target cells. These drugs bind HCV E2 in a reversible manner and block HCV E2 interaction with CD81 while having no effect on CD81 expression nor on CD81-interaction with physiological partner molecules (106). However, data of the effect of these drugs on HCVcc infection are not yet available. Recently, SR-BI has been demonstrated to bind and internalize serum amyloid A (SAA), an acute phase protein mainly produced in the liver and known to mediate pro-inflammatory cellular responses (107, 108). SAA was shown to inhibit HCV entry by interacting with the virus thereby reducing its infectivity (109). Thus, SAA analogues might present potent anti-HCV activity. In addition to small molecule inhibitors, peptides that mimic conserved regions of HCV E2 interacting with cell entry receptors may also provide an interesting approach to prevent HCV infection but have weaknesses as drugs because they are not orally available and expensive to produce.

Fusion inhibitors

Insights into the molecular mechanisms of HCV fusion are just about to arise and molecules likely to interfere with HCV penetration have not yet been described. As HCV enters the host cell through endocytosis and requires low pH for delivery of HCV genome, agents preventing the acidification of endosomal compartments, such as chloroquine, are able to prevent infection (72, 79). Potential targets for anti-fusion drugs might arise in the next few years while insights into HCV fusion process are growing. Peptide-based fusion inhibitors have already been established for the treatment of other viral infections such as HIV infection. Enfuvirtide which blocks HIV fusion to host cells is the first compound of this family approved for clinical use (110).