Substitution of proline with pipecolic acid at the scissile bond converts a peptide substrate of HIV proteinase into a selective inhibitor.
The nonapeptide H-Val-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-NH2 containing the retroviral Tyr-Pro cleavage site is a good substrate for the proteinase of human immunodeficiency viruses but it is not readily hydrolyzed by other nonviral proteinases including the structurally related pepsin-like aspartic proteinases. Replacing the Pro by L-pipecolic acid (2-piperidinecarboxylic acid) converted the substrate into an effective inhibitor of HIV-1 and HIV-2 proteinases with IC50 of approximately 1 microM. This compound showed a high degree of selectivity in that it did not inhibit cathepsin D and renin.
Laboratory of Molecular Virology and Carcinogenesis, NCI-Frederick Cancer Research and Development Center, Maryland 21701.
T D
TD
Copeland
E M
EM
Wondrak
J
J
Tozser
M M
MM
Roberts
S
S
Oroszlan
D000595:Amino Acid Sequence; D010450:Endopeptidases / Q000378:metabolism*; D015684:Gene Products, pol / Q000378:metabolism*; D016333:HIV Protease; D015497:HIV-1 / Q000201:enzymology*; D015498:HIV-2 / Q000201:enzymology*; D006801:Humans; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010875:Pipecolic Acids; D011392:Proline; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*
D015684:Gene Products, pol; D009842:Oligopeptides; D010875:Pipecolic Acids; D011480:Protease Inhibitors; D011392:Proline; D010450:Endopeptidases; D016333:HIV Protease; C031345:pipecolic acid