Prenylation of HDAg and antiviral drug development

Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, CA 94305-5187, USA.
Current topics in microbiology and immunology (Impact Factor: 4.1). 02/2006; 307:133-49. DOI: 10.1007/3-540-29802-9_7
Source: PubMed


Hepatitis delta virus (HDV) is an important cause of acute and chronic liver disease. Current medical therapies are unable to effectively eradicate HDV infections. Research into the molecular virology of the HDV life cycle has revealed a fascinating collection of biology. These insights are now beginning to be translated into new potential treatment strategies. For example, an essential step in the virus assembly process involves the post-translational lipid modification of a specific HDV protein, namely prenylation of large delta antigen. Preventing prenylation abolishes virus particle formation. Drugs capable of specifically inhibiting prenylation have been developed for use in humans. These agents represent a new class of antiviral agents, with HDV as a first target. Here, a brief review of the HDV life cycle emphasizing the role of prenylation is presented along with implications for drug development and therapy.

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    • "Interestingly, lamivudine-induced mutations in the polymerase region, which confer HBV resistance to this therapy, are associated with changes in the overlapping envelope gene products; a change in SW 196 L/S of the small HBsAg, carried by mutation M 204 I in the reverse transcriptase of HBV, was found to inhibit the secretion of HDV particles in cell cultures, suggesting that lamivudine therapy may indirectly abrogate an underlying HDV infection [91]. On the HDV side, critical to the interaction of LHD- Ag with the HBV envelope protein is farnesylation (prenylation ), of the last four aminoacids Cys-Arg-Pro-Gln- COOH on the LHD-Ag (so-called CXXX box; C for cysteine, X for any amino-acid) [92]. By preventing the association of the HDV ribonucleoprotein with the HBsAg and, therefore, virion assembly, disruption of prenylation might form the basis of a new therapeutic strategy against HDV; experiments in vitro have shown that HDAg prenylation can be inhibited by the prenylation inhibitor BZA-5B and in vivo the prenylation inhibitors FTI – 277 and FTI – 2153 were highly effective at clearing HD viremia in a mouse model of HDV infection [93] "
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