Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor: A platform for antiviral drug design

HIV integrase, the enzyme that inserts the viral DNA into the host chromoso me, has no mammalian counterpart, making it an attractive target for antivi ral drug design. As one of the three enzymes produced by HIV, it can be exp ected that inhibitors of this enzyme will complement the therapeutic use of HIV protease and reverse transcriptase inhibitors, We have determined the structure of a complex of the HIV-1 integrase core domain with a novel inhi bitor, 5CITEP, 1-(5-chloroindol-3-yl)-3-hydroxy-3-(2H-tetrazole-5-yl)-pro-p enone, to 2.1-Angstrom resolution. The inhibitor binds centrally in the act ive site of the integrase and makes a number of close contacts with the pro tein. Only minor changes in the protein accompany inhibitor binding. This i nhibitor complex will provide a platform for structure-based design of an a dditional class of inhibitors for antiviral therapy.