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Abstract
Grant Number: 1R43AI057074-01 PI Name: PETROPOULOS, CHRISTOS J. PI Email: cpetropoulos@virologic.com PI Title: VICE PRESIDENT, RESEARCH Project Title: ASSAYS FOR MEASURING THE INHIBITION OF HIV-1 ENZYMES Abstract: DESCRIPTION (provided by applicant): Currently approved drugs inhibit HIV-1 replication by interfering with the enzymatic activities of either protease (PR) or reverse transcriptase (RT). The ability of HIV to rapidly evolve drug resistance, together with the toxicity problems of current antiretroviral regimens, requires the development of additional classes of antiviral drugs. As an essential enzyme for HIV-1 replication, Integrase (IN) is an attractive antiviral target. Recent technological advances have resulted in the identification of good lead compounds that could serve as the starting point for structure-based Integrase Inhibitor (INI) design. Clinical evaluation of some of these compounds is underway. The overall goal of this project is to develop rapid, sensitive phenotypic and genotypic assays to evaluate the susceptibility of HIV-1 isolates to inhibitors of all HIV-1 viral enzymes, with particular emphasis on INIs. We will construct two alternative vector systems that produce virus particles containing HIV-1 pol proteins derived from patient isolates. These assays will be based on the technology underlying PhenoSense HIVTM, an existing cell-based antiviral drug susceptibility assay that evaluates PR and RT inhibitors. At the completion of Phase I, we will be able to provide Research Use Only (RUO) assays to pharmaceutical companies developing inhibitors of any pol enzymatic function. In addition to aiding in the discovery and development of first generation INIs by characterizing resistance in vitro, the RUO assays will assist in the discovery and development of second-generation drugs that are active against drug resistant strains by screening new drug candidates against a library of resistance test vectors. Additionally, the RUO assays will allow monitoring the development of IN inhibitor resistant HIV-1 during the clinical evaluation of investigational agents. Characterizing the performance of these RUO assays during Phase I will facilitate their clinical validation as Phase II of the project. For the selection of potent antiretroviral treatment regimens that include combinations of active PR, RT and IN inhibitors.
Thesaurus Terms:
bioassay, enzyme inhibitor, human immunodeficiency virus 1, integrase, technology /technique development, transfection /expression vector
DNA primer, drug resistance, enzyme activity, genetic transcription, nucleic acid sequence, protease inhibitor, reverse transcriptase inhibitor, viremia, virus replication
biotechnology, clinical research, human tissue, nucleic acid amplification technique, plasma, tissue /cell culture
Institution: VIROLOGIC, INC. 345 OYSTER POINT BLVD SOUTH SAN FRANCISCO, CA 94080 Fiscal Year: 2003 Department: Project Start: 01-JUL-2003 Project End: 30-JUN-2005 ICD: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES IRG: ZRG1
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