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
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 . 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) . 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  "
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ABSTRACT: The key to the discovery of the Hepatitis D Virus (HDV) was the description in Turin, Italy in the mid-1970s of the delta antigen and antibody in carriers of the hepatitis B surface antigen. The new antigen was first thought to be a marker of the Hepatitis B Virus (HBV) and in view of its intricate true nature, it would have possibly died away as another odd antigenic subtype of HBV, like many that were described in the 1970s. Fortunately, instead, a collaboration started in 1978 between the Turin group, and the National Institute of Health and Georgetown University in the US. With American facilities and expertise this collaboration led just a year later, in 1979, to the unfolding of an unexpected and amazing chapter in virology. Experiments in chimpanzees demonstrated that the delta antigen was not a component of the HBV but of a separate defective virus requiring HBV for its infection; it was named the hepatitis D virus to conform to the nomenclature of hepatitis viruses and classified within the genus Deltavirus. The animal experiments were also seminal in proposing to future clinical interpretation, the paradigm of a pathogenic infection (hepatitis D), that could develop only in HBV-infected patients, was mainly transmitted by superinfection of HDV on chronic HBV carriers and had the ability to strongly inhibit the helper HBV. The discovery of the HDV has driven three directions of further research: (1) The understanding of the replicative and infectious mechanisms of the HDV. (2) The assessment of its epidemiological and medical impact. (3) The search for a therapy for chronic hepatitis D (CHD). This review summarizes the progress achieved in each field of research in the thirty years that have passed since the discovery of HDV.
Journal of Hepatology 03/2009; 50(5):1043-50. DOI:10.1016/j.jhep.2009.01.004 · 11.34 Impact Factor
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ABSTRACT: Coinfection of hepatitis B virus (HBV) with HIV, hepatitis C virus (HCV) and hepatitis D virus (HDV) is common because of shared modes of transmission. Increasing prevalence of high risk sexual behavior and intra venous drug use (IVDU) contributes to a majority of the cases with coinfection. Occult HBV or prior HBV infection is frequently encountered in patients coinfected with HIV or HCV. Although HBV is a preventable disease, failure to screen and inadequate vaccination in the high risk individuals account for vast under-recognition of the cases with HBV infection. Chronic liver disease from viral hepatitis B and C has emerged as the major cause of morbidity and mortality worldwide as well as in the United States. This is especially true in cases coinfected with HIV. The potential long term risks of untreated hepatitis include cirrhosis and hepatocellular carcinoma. There have been several advancements in the understanding of natural history and management options of chronic viral hepatitis. This article discusses and reviews the natural history, epidemiology, and management of HBV patients coinfected with HIV, HCV, or HDV. It includes an updated summary of the outcomes with liver transplantation and post transplant recurrence in the coinfected population with HBV. It also discusses the role of occult HBV in HIV and HCV coinfection respectively.
Current Hepatitis Reports 12/2011; 10(4). DOI:10.1007/s11901-011-0115-1
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ABSTRACT: We developed two-dimensional photonic crystal slab laser with a modified linear shaped donor-type point defect for ultrahigh Q cavity. A device characteristic is found to be dramatically improved by the modification of the defect structure.
Lasers and Electro-Optics, 2003. CLEO/Pacific Rim 2003. The 5th Pacific Rim Conference on; 01/2004
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