Hazuda DJ; HIV DRP Symposium Understanding Antiviral Drug Resistance.
Program Abstr HIV DRP Symp Underst Antivir Drug Resist 1st 2000 Chantilly Va. 2000 Dec 3-6; 1: Abstract no. 66.
Department of Antiviral Research, Merck Research Laboratories, West Point, PA
Integrase is the third of the virally encoded enzymes of HIV-1 and the only one for which clinical agents have not yet been developed. Integrase catalyzes the integration of the HIV-1 DNA into the genome of the host cell. Integration is essential for HIV-1 replication and presents a substantial opportunity for the development of novel chemotherapeutic agents. Integrase is the only protein known to be required to catalyze each of the specific steps required for integration which include 1) assembly of a stable complex with the viral DNA, 2) 3' processing of the viral DNA ends, and 3) strand transfer or joining of the viral and cellular DNAs. While many inhibitors of integrase have been described, DKAs were recently shown to be the first biologically active inhibitors of integration as validated by both careful analysis of mechanism in infected cells and resistance. The DKAs are selective inhibitors of strand transfer in vitro and exert their effect on HIV-1 replication exclusively as a result of inhibiting the strand transfer reaction in the infected cell; it is therefore intriguing to speculate that the DKAs are effective antiviral agents due to this unique mechanism of action. Recent insights into the mechanism of action of the DKAs as strand transfer inhibitors of integrase will be discussed relative to the requirements for binding and inhibitory activity using a variety of structural analogs in studies comparing the wild type integrase and DKA resistant variants.
Publication Types:
Keywords:
- Antiviral Agents
- Catalysis
- DNA
- DNA Nucleotidyltransferases
- DNA, Viral
- HIV Integrase
- HIV-1
- In Vitro
- Integrases
- antagonists & inhibitors
Other ID:
UI: 102249558
From Meeting Abstracts