title: Disulfide-constrained peptides that bind to the extracellular portion of the prostate-specific membrane antigen.
abstract: The prostate-specific membrane antigen (PSMA) is a well-characterized surface antigen, overexpressed in the most advanced, androgen-resistant human prostate cancer cells. We sought to exploit PSMA cell surface properties as a target for short peptides that will potentially guide protein-based therapeutics, such as viral vectors, to prostate cancer cells. Two separate phage display peptide strategies were applied, in parallel, to purified PSMA protein bound to two separate substrates. We reasoned that peptide sequences common to both substrate selections would be specific binders of PSMA. Additionally, the design allowed for stringent cross-selections, where phage populations from one selection condition could be applied to the alternative substrate. These strategies resulted in a series of phage displayed peptides able to bind to PSMA by ELISA and direct binding assays, both with purified protein and in prostate cancer cells. Cell binding is competitively inhibited by purified PSMA. The synthesized peptides are capable of enhancing PSMA carboxypeptidase enzymatic activity, suggesting protein folding stabilization. The discovery of these peptides provides the foundation for subsequent development of peptide targeted therapeutics against prostate cancer.
authors.affiliation: James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-2101, USA. slupold@jhmi.edu
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Lupold
authors.forename: Ronald
authors.initials: R
authors.lastname: Rodriguez
mesh_terms: D000595:Amino Acid Sequence; D000954:Antigens, Surface / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004220:Disulfides / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D043425:Glutamate Carboxypeptidase II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein
chemical_list: D000954:Antigens, Surface; D004220:Disulfides; D008565:Membrane Proteins; D019151:Peptide Library; D010455:Peptides; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II