title: Design, synthesis, and structure-activity relationship studies of a potent PACE4 inhibitor.
abstract: PACE4 plays an important role in the progression of prostate cancer and is an attractive target for the development of novel inhibitor-based tumor therapies. We previously reported the design and synthesis of a novel, potent, and relatively selective PACE4 inhibitor known as a Multi-Leu (ML) peptide. In the present work, we examined the ML peptide through detailed structure-activity relationship studies. A variety of ML-peptide analogues modified at the P8-P5 positions with leucine isomers (Nle, DLeu, and DNle) or substituted at the P1 position with arginine mimetics were tested for their inhibitory activity, specificity, stability, and antiproliferative effect. By incorporating d isomers at the P8 position or a decarboxylated arginine mimetic, we obtained analogues with an improved stability profile and excellent antiproliferative properties. The DLeu or DNle residue also has improved specificity toward PACE4, whereas specificity was reduced for a peptide modified with the arginine mimetic, such as 4-amidinobenzylamide.
authors.affiliation: Institut de Pharmacologie de Sherbrooke, Department of Surgery/Urology Division, Université de Sherbrooke , 3001 12th Avenue North, Sherbrooke, Québec, J1H 5N4, Canada .
authors.forename: Anna
authors.initials: A
authors.lastname: Kwiatkowska
authors.forename: Frédéric
authors.initials: F
authors.lastname: Couture
authors.forename: Christine
authors.initials: C
authors.lastname: Levesque
authors.forename: Kévin
authors.initials: K
authors.lastname: Ly
authors.forename: Roxane
authors.initials: R
authors.lastname: Desjardins
authors.forename: Sophie
authors.initials: S
authors.lastname: Beauchemin
authors.forename: Adam
authors.initials: A
authors.lastname: Prahl
authors.forename: Bernard
authors.initials: B
authors.lastname: Lammek
authors.forename: Witold
authors.initials: W
authors.lastname: Neugebauer
authors.forename: Yves L
authors.initials: YL
authors.lastname: Dory
authors.forename: Robert
authors.initials: R
authors.lastname: Day
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D004355:Drug Stability; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012697:Serine Endopeptidases; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D011480:Protease Inhibitors; C080654:PCSK6 protein, human; D043484:Proprotein Convertases; D012697:Serine Endopeptidases