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Access Type

WSU Access

Date of Award

January 2012

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Biochemistry and Molecular Biology

First Advisor

Ladislau C. Kovari

Abstract

The antiviral drug development has improved steadily to treat the infections of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) which represent heavy public health burdens. The viral protease plays an indispensable role in viral maturation and therefore becomes one of the most important targets for drug design. Nine HIV-1 protease inhibitors and two HCV protease inhibitors have been developed and approved by the U.S. Food and Drug Administration. However, mutations in the protease decrease reduce the efficacy the drugs. In this study, the enzyme assays indicate that darunavir and tipranavir exhibit the most potent inhibition against the multi-drug resistant (MDR) HIV-1 protease, which is supported by the co-crystal structures of the MDR protease-darunavir complex and the MDR protease-tipranavir complex. The MDR HIV-1 protease not only decreases the susceptibility to drugs but also impedes the formation of protease-substrate complex. Molecular dynamics simulation results show that the MDR HIV-1 protease needs to conquer a higher desolvation energy barrier to bind the substrate. Besides the study of drug resistance mechanisms, two drug discovery methods have been carried out in the study. One method is the modification of a current drug, lopinavir. The potency of the lopinavir analog against the MDR HIV-1 protease increases. The other method is the identification of a novel HIV-1 protease inhibitor scaffold to increase the structural diversity of inhibitors. In the HCV section, the study focuses on an HCV NS3/4A protease inhibitor, telaprevir, which is approved for the treatment of patients infected with the HCV genotype 1. The enzyme assays and molecular dynamic studies suggest that telaprevir may retain sufficient potency to treat the non-genotype 1 HCV strains.