Substitution of proline with pipecolic acid at the scissile bond converts a peptide substrate of HIV proteinase into a selective inhibitor

Biochem Biophys Res Commun. 1990 May 31;169(1):310-4. doi: 10.1016/0006-291x(90)91469-9.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Endopeptidases / metabolism*
  • Gene Products, pol / metabolism*
  • HIV Protease
  • HIV-1 / enzymology*
  • HIV-2 / enzymology*
  • Humans
  • Molecular Sequence Data
  • Oligopeptides / chemical synthesis
  • Oligopeptides / pharmacology*
  • Pipecolic Acids
  • Proline
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / pharmacology*

Substances

  • Gene Products, pol
  • Oligopeptides
  • Pipecolic Acids
  • Protease Inhibitors
  • Proline
  • Endopeptidases
  • HIV Protease
  • pipecolic acid