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 genome 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 combinatorial library." We identified a hexapeptide with the sequence HCKFWW that inhibits IN-mediated 3'-processing and integration with an IC50 of 2 microM. The peptide is active on IN proteins from other retroviruses such as HIV-2, feline immunodeficiency virus, and Moloney murine leukemia virus, supporting the notion that a conserved region of IN is targeted. The hexapeptide was also tested in the disintegration reaction. This phosphoryl-transfer reaction can be carried out by the catalytic core of IN alone, and the peptide HCKFWW was found to inhibit this reaction, suggesting that the hexapeptide acts at or near the catalytic site of IN. Identification of an IN hexapeptide inhibitor provides proof of concept for the approach, and, moreover, this peptide may be useful for structure-function analysis of IN.
Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
R A
RA
Puras Lutzke
N A
NA
Eppens
P A
PA
Weber
R A
RA
Houghten
R H
RH
Plasterk
D000595:Amino Acid Sequence; D004254:DNA Nucleotidyltransferases / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics; D015498:HIV-2 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D016089:Immunodeficiency Virus, Feline / Q000187:drug effects / Q000235:genetics; D019426:Integrases; D008969:Molecular Sequence Data; D008979:Moloney murine leukemia virus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D012190:Retroviridae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D013329:Structure-Activity Relationship; D016662:Virus Integration / Q000187:drug effects*
D004791:Enzyme Inhibitors; D009842:Oligopeptides; D004254:DNA Nucleotidyltransferases; D019426:Integrases