Potent and Selective Peptidyl Boronic Acid Inhibitors of the Serine Protease Prostate-Specific Antigen

Aaron M. LeBeau, Pratap Singh, John T. Isaacs, Samuel R. Denmeade

Research output: Contribution to journalArticlepeer-review

Abstract

Prostate cancer cells produce high (microgram to milligram/milliliter) levels of the serine protease Prostate-Specific Antigen (PSA). PSA is enzymatically active in the extracellular fluid surrounding prostate cancers but is found at 1,000- to 10,000-fold lower concentrations in the circulation, where it is inactivated due to binding to abundant serum protease inhibitors. The exclusive presence of high levels of active PSA within prostate cancer sites makes PSA an attractive candidate for targeted imaging and therapeutics. A synthetic approach based on a peptide substrate identified first peptide aldehyde and then boronic acid inhibitors of PSA. The best of these had the sequence Cbz-Ser-Ser-Lys-Leu-(boro)Leu, with a Ki for PSA of 65 nM. The inhibitor had a 60-fold higher Ki for chymotrypsin. A validated model of PSA's catalytic site confirmed the critical interactions between the inhibitor and residues within the PSA enzyme.

Original languageEnglish (US)
Pages (from-to)665-674
Number of pages10
JournalChemistry and Biology
Volume15
Issue number7
DOIs
StatePublished - Jul 21 2008

Keywords

  • CHEMBIO
  • PROTEINS

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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