HIV integrase: a target for drug discovery

Abstract

Current antiviral strategies against HIV rely on structure-function analysis of HIV reverse transcriptase (RT) and protease (PR). The third viral pol gene product, HIV integrase (IN), is also a good target for drug discovery, since IN is essential for retroviral replication and, moreover, it has no obvious functional analogue in the host. IN forms a ternary complex with metal ions and DNA and has a mechanism of catalysis common with other polynucleotidyl transferases. Although there is no structural information for full-length IN available, structures of all three functional IN domains have been determined by X-ray crystallography and NMR spectroscopy. The N-terminal domain has a novel zinc-binding fold, the catalytic domain shares a common structural motif with other polynucleotidyl transferases, and the C-terminal DNA-binding domain has a Src-homology-3-like fold. This structural information provides the basis for drug development. In turn, increasing numbers of IN inhibitors identified so far may serve structure-function analysis of IN. The final goal is the development of new classes of anti-HIV drugs, which can be added to the repertoire of anti-RT and anti-PR drugs.