Prenylation of HDAg and Antiviral Drug Development

Division of Gastroenterology and Hepatology, Stanford University School of Medicine, CCSR 3115, 269 Campus Drive, Palo Alto, CA 94305-5187, USA [email protected]

1 Introduction 134

1.1 HDV Disease Burden 134

1.2 The HDV Virion 134

1.3 The HDV Life Cycle 135

2 Prenylation and HDV Assembly 136

3 Targeting HDV Assembly by Prenylation Inhibition 138

3.1 Inadequacy of Current Therapy for HDV 138

3.2 Prenylation Inhibition—Effect on HDV VLPs 138

3.3 Prenylation Inhibition-Effect on Infectious HDV Particles 139

3.4 Prenylation Inhibition—In Vivo Efficacy 139

4 Prenylation Inhibition - Rationale for Human HDV Infections 140

5 Attractive Features of Prenylation Inhibition-Based Antiviral Therapy . . 141

6 Other Targets for Anti-HDV Therapy 143

References 145

Abstract 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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