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The Multi-Leu Peptide Inhibitor Discriminates Between PACE4 And Furin And Exhibits Antiproliferative Effects On Prostate Cancer Cells
Christine Levesque , Martin Fugère , Anna Kwiatkowska , Frédéric Couture , Roxane Desjardins , Sophie Routhier , Philippe Moussette , Adam Prahl , Bernard Lammek , Jon R Appel , Richard A. Houghten , François D’Anjou , Yves L. Dory , Witold Neugebauer , and Robert Day
J. Med. Chem., Just Accepted Manuscript
DOI: 10.1021/jm3011178
Publication Date (Web): November 5, 2012
Copyright © 2012 American Chemical Society

The proprotein convertases (PCs) plays 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.