HIV‐1 integrase inhibitors: 2003–2004 update

Abstract

The integration of viral cDNA into the host genome is an essential step in the HIV-1-life cycle and is mediated by the virally encoded enzyme, integrase (IN). Inhibition of this process provides an attractive strategy for antiviral drug design. The discovery of beta-diketo acid inhibitors played a major role in validating IN as a legitimate antiretroviral drug target. Over a decade of research, a plethora of IN inhibitors have been discovered and some showed antiviral activity consistent with their effect on IN. To date, at least two compounds have been tested in human but none are close to the FDA approval. In this review, we provide a comprehensive report of all small-molecule IN inhibitors discovered during the years 2003 and 2004. Compilation of such data will prove beneficial in developing QSAR, virtual screening, pharmacophore hypothesis generation, and validation.

Crystal structure of (Z)-3-hydroxy-3-(4-methoxyphenyl)-1-(pyridin-2-yl)prop-2-en-1-one, C15H13NO3

“…Compounds incorporating a β-ketoenol moiety have yielded clinical integrase inhibitor drug candidates [1]. Tomassini et al reported a series of β-ketoenol derivatives as e ective inhibitors drug of in uenza viral replication in both in vitro cell culture replication assays and in vivo mouse challenge model, without exhibiting any cytotoxicity [2][3][4].…”

Single amino acid substitution in HIV‐1 integrase catalytic core causes a dramatic shift in inhibitor selectivity

“…[3][4][5]). Using this in vitro method we present here the activity of six small molecule IN inhibitors from five different structural classes tested against wild type (WT) IN, a soluble double mutant (F185K/ C280S) protein (SM), and two other IN mutants containing an additional substitution at position C130 (Ala and Ser).…”

Probing HIV-1 Integrase Inhibitor Binding Sites with Position-Specific Integrase-DNA Cross-Linking Assays

“…Many integrase inhibitors have been discovered during the past 10 years, with two of them presently in clinical trials (for review, see Pommier et al, 2005;Dayam et al, 2006;DeJesus et al, 2006;Semenova et al, 2006b). The binding sites of only two inhibitors, 5CITEP and Y-3, have been determined by X-ray crystallography (Lubkowski et al, 1998;Goldgur et al, 1999).…”