title: Optimization of peptide-based inhibitors of prostate-specific antigen (PSA) as targeted imaging agents for prostate cancer.
abstract: Prostate-specific antigen (PSA) is a serine protease biomarker that may play a role in prostate cancer development and progression. The inhibition of PSA's enzymatic activity with small molecule inhibitors is an attractive and, as of yet, unexploited target. Previously, we reported a series of peptidyl aldehyde and boronic acid based inhibitors of PSA. In this study, the structural requirements in the P2 and P3 positions of peptide-based PSA inhibitors are explored through the substitution of a series of natural and unnatural amino acids in these positions. This analysis demonstrated a preference for hydrophobic residues in the P2 position and amino acids with the potential to hydrogen bond in the P3 position. Using this information, a peptide boronic acid inhibitor with the sequence Cbz-Ser-Ser-Gln-Nle-(boro)-Leu was identified with a K(i) for PSA of 25nM. The attachment of a bulky metal chelating group to the amino terminal of this peptide did not adversely affect PSA inhibition. This result suggests that a platform of PSA inhibitor chelates could be developed as SPECT or PET-based imaging agents for prostate cancer.
authors.affiliation: Department of Pharmacology and Molecular Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: LeBeau
authors.forename: Sangeeta R
authors.initials: SR
authors.lastname: Banerjee
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.forename: Ronnie C
authors.initials: RC
authors.lastname: Mease
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Denmeade
mesh_terms: D000595:Amino Acid Sequence; D001897:Boronic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003952:Diagnostic Imaging; D006801:Humans; D008297:Male; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000201:enzymology*; D012661:Semen / Q000737:chemistry; D013379:Substrate Specificity
chemical_list: D001897:Boronic Acids; D019151:Peptide Library; D010455:Peptides; D017430:Prostate-Specific Antigen