HIV-1 integrase is a
protein of Mr 32 000 encoded at the 3'-end of the pol gene. Integration of HIV
DNA into the host cell chromosomal
DNA apparently occurs by a carefully defined sequence of
DNA tailoring (3'-processing (3'P)) and coupling (integration) reactions. Integration of HIV
DNA into human
DNA represents the biochemical completion of the invasion of the human cell (e.g., T-cell) by HIV. Unlike major successes seen in the development of clinically approved
anti-HIV agents against
HIV reverse transcriptase and
HIV protease, there are no FDA-approved
anti-HIV 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, bis-diketo
acids, functionalised
naphthyridines and other isosteres of diketo
acids. Data pertaining to
integrase inhibition and in vitro anti-HIV activity are discussed. Mention is made of drugs in clinical trials, both past (
S-1360, L-870,810 and L-870,812 and present (
GS-9137 and
MK-0518). Other promising drugs, including those from the authors' laboratory, are referred. Resistant mutants arising from key
integrase inhibitors and cross-resistance are indicated.