title: The hunt for HIV-1 integrase inhibitors.
abstract: Currently, there are three distinct mechanistic classes of antiretrovirals: inhibitors of the HIV- 1 reverse transcriptase and protease enzymes and inhibitors of HIV entry, including receptor and coreceptor binding and cell fusion. A new drug class that inhibits the HIV-1 integrase enzyme (IN) is in development and may soon be available in the clinic. IN is an attractive drug target because it is essential for a stable and productive HIV-1 infection and there is no mammalian homologue of IN. Inhibitors of integrase enzyme (INI) block the integration of viral double-stranded DNA into the host cell's chromosomal DNA. HIV-1 integration has many potential steps that can be inhibited and several new compounds that target specific integration steps have been identified by drug developers. Recently, two INIs, GS-9137 and MK-0518, demonstrated promising early clinical trial results and have been advanced into later stage trials. In this review, we describe how IN facilitates HIV-1 integration, the needed enzyme cofactors, and the resultant byproducts created during integration. Furthermore, we review the different INIs under development, their mechanism of actions, site of IN inhibition, potency, resistance patterns, and discuss the early clinical trial results.
authors.affiliation: Division of Infectious Diseases, Yale University School of Medicine, LLCI 100D, 300 Cedar Street, Suite 169, New Haven, Connecticut 06520, USA. Max.Lataillade@yahle.edu
authors.forename: Max
authors.initials: M
authors.lastname: Lataillade
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kozal
mesh_terms: D015195:Drug Design; D004341:Drug Evaluation; D004791:Enzyme Inhibitors; D019427:HIV Integrase / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D016662:Virus Integration / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D019427:HIV Integrase