Abstract
HIVโ1 integrase is a protein of Mr 32โ000 encoded at the 3โฒโend of the pol gene. Integration of HIV DNA into the host cell chromosomal DNA apparently occurs by a carefully defined sequence of DNA tailoring (3โฒโprocessing (3โฒP)) and coupling (integration) reactions. Integration of HIV DNA into human DNA represents the biochemical completion of the invasion of the human cell (e.g., Tโcell) by HIV. Unlike major successes seen in the development of clinically approved antiโHIV agents against HIV reverse transcriptase and HIV protease, there are no FDAโapproved antiโHIV drugs in clinical use where the mechanism of action is inhibition of HIV integrase. This review summarises some key advances in the area of integrase inhibitors with the major focus being on new generation inhibitors. Special emphasis is placed on diketo acids with aromatic and heteroaromatic moieties, diketo acids with nucleobase scaffolds, bisโdiketo acids, functionalised naphthyridines and other isosteres of diketo acids. Data pertaining to integrase inhibition and in vitro antiโHIV activity are discussed. Mention is made of drugs in clinical trials, both past (Sโ1360, Lโ870,810 and Lโ870,812 and present (GSโ9137 and MKโ0518). Other promising drugs, including those from the authors' laboratory, are referred. Resistant mutants arising from key integrase inhibitors and crossโresistance are indicated. Copyright ยฉ 2007 John Wiley & Sons, Ltd.