The proprotein convertases (PCs) play an important role in protein precursor activation through processing at paired basic residues.
However, significant substrate cleavage redundancy has been reported between PCs. The question remains whether specific PC inhibitors can be designed. This study describes the identification of the sequence LLLLRVKR, named Multi-Leu (ML)-peptide, that displayed a 20-fold selectivity on PACE4 over furin, two enzymes with similar structural characteristics. We have previously demonstrated that PACE4 plays an important role in prostate cancer and could be a druggable target. The present study demonstrates that the ML-peptide significantly reduced the proliferation of DU145 and LNCaP prostate cancer-derived cell lines and induced G0/G1 cell cycle arrest. However, the ML-peptide must enter the cell to inhibit proliferation. It is concluded that peptide-based inhibitors can yield specific PC inhibitors and that the ML-peptide is an important lead compound that could potentially have applications in prostate cancer.
Written by:
Levesque C, Fugère M, Kwiatkowska A, Couture F, Desjardins R, Routhier S, Moussette P, Prahl A, Lammek B, Appel JR, Houghten RA, D'Anjou F, Dory YL, Neugebauer W, Day R. Are you the author?
Institut de Pharmacologie de Sherbrooke, Département de Chirurgie/Urologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, 3001 12e Avenue Nord, Sherbrooke, Québec J1H 5N4, Canada.
Reference: J Med Chem. 2012 Dec 13;55(23):10501-11.
doi: 10.1021/jm3011178
PubMed Abstract
PMID: 23126600
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