IDENTIFICATION OF A HEXAPEPTIDE INHIBITOR OF THE HUMAN-IMMUNODEFICIENCY-VIRUS INTEGRASE PROTEIN BY USING A COMBINATORIAL CHEMICAL LIBRARY

Integration of human immunodeficiency virus (HIV) DNA into the human g enome requires the virus-encoded integrase (IN) protein, and therefore the IN protein is a suitable target for antiviral strategies. To find a potent HIV IN inhibitor, we screened a ''(synthetic peptide combina torial library.'' We identified a hexapeptide with the sequence HCKFWW that inhibits IN-mediated 3'-processing and integration with an IC50 of 2 mu M. The peptide is active on IN proteins from other retroviruse s such as HIV-2, feline immunodeficiency virus, and Moloney murine leu kemia virus, supporting the notion that a conserved region of IN is ta rgeted. The hexapeptide was also tested in the disintegration reaction , This phosphoryl-transfer reaction can be carried out by the catalyti c core of IN alone, and the peptide HCKFWW was found to inhibit this r eaction, suggesting that the hexapeptide acts at or near the catalytic site of IN. Identification of an IN hexapeptide inhibitor provides pr oof of concept for the approach, and, moreover, this peptide may be us eful for structure-function analysis of IN.