title: The Multi-Leu peptide inhibitor discriminates between PACE4 and furin and exhibits antiproliferative effects on prostate cancer cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Christine
authors.initials: C
authors.lastname: Levesque
authors.forename: Martin
authors.initials: M
authors.lastname: Fugère
authors.forename: Anna
authors.initials: A
authors.lastname: Kwiatkowska
authors.forename: Frédéric
authors.initials: F
authors.lastname: Couture
authors.forename: Roxane
authors.initials: R
authors.lastname: Desjardins
authors.forename: Sophie
authors.initials: S
authors.lastname: Routhier
authors.forename: Philippe
authors.initials: P
authors.lastname: Moussette
authors.forename: Adam
authors.initials: A
authors.lastname: Prahl
authors.forename: Bernard
authors.initials: B
authors.lastname: Lammek
authors.forename: Jon R
authors.initials: JR
authors.lastname: Appel
authors.forename: Richard A
authors.initials: RA
authors.lastname: Houghten
authors.forename: François
authors.initials: F
authors.lastname: D'Anjou
authors.forename: Yves L
authors.initials: YL
authors.lastname: Dory
authors.forename: Witold
authors.initials: W
authors.lastname: Neugebauer
authors.forename: Robert
authors.initials: R
authors.lastname: Day
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D045683:Furin / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D011994:Recombinant Proteins / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases
chemical_list: D009842:Oligopeptides; D011994:Recombinant Proteins; C080654:PCSK6 protein, human; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D045683:Furin