HIV integrase: a target for drug discovery.
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.
Lutzke
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Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Plasterk
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D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002384:Catalysis; D020134:Catalytic Domain; D004247:DNA / Q000378:metabolism; D015195:Drug Design; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D004247:DNA; D019427:HIV Integrase