Identification of a small-molecule binding site at the dimer interface of the HIV integrase catalytic domain

Integration of the reverse-transcribed HIV cDNA into the host DNA is a requ ired step in viral replication. The virus-encoded integrase protein catalyz es the initial DNA breaking and joining reactions that mediate cDNA integra tion. Here, the identification by X-ray crystallography of a small-molecule binding site on the integrase catalytic domain is reported. The small-mole cule family studied consists of a core of arsenic or phosphorus surrounded by four aromatic groups. Two arsenic derivatives were visualized bound to i ntegrase. In each case, two molecules bound at symmetry-related sites on th e catalytic domain dimer interface. The first compound studied, tetraphenyl arsonium, did not inhibit integrase. However, a synthetic compound substit uting a catechol for one of the phenyl rings, dihydroxyphenyltriphenylarson ium, bound to the same site and did inhibit the enzyme. Changes in the vici nity of the catalytic site were seen with the inhibitory compound only, pot entially explaining its mechanism of action. Further substituting phosphoni um for arsonium yielded a compound with an IC50 in the low micromolar range . These findings may be useful in designing new inhibitors of integrase, wh ich is at present the only one of the three HIV enzymes for which clinicall y useful inhibitors are not available.