Optimization of peptide-based inhibitors of prostate-specific antigen (PSA) as targeted imaging agents for prostate cancer
- Bioorg Med Chem. 2009 Jul 15;17(14):4888-93. doi: 10.1016/j.bmc.2009.06.012.
- 1. Department of Pharmacology and Molecular Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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.