title: Novel Insights into Structure-Activity Relationships of N-Terminally Modified PACE4 Inhibitors.
abstract: PACE4 plays important roles in prostate cancer cell proliferation. The inhibition of this enzyme has been shown to slow prostate cancer progression and is emerging as a promising therapeutic strategy. In previous work, we developed a highly potent and selective PACE4 inhibitor, the multi-Leu (ML) peptide, an octapeptide with the sequence Ac-LLLLRVKR-NH2 . Here, with the objective of developing a useful compound for in vivo administration, we investigate the effect of N-terminal modifications. The inhibitory activity, toxicity, stability, and cell penetration properties of the resulting analogues were studied and compared to the unmodified inhibitor. Our results show that the incorporation of a polyethylene glycol (PEG) moiety leads to a loss of antiproliferative activity, whereas the attachment of a lipid chain preserves or improves it. However, the lipidated peptides are significantly more toxic when compared with their unmodified counterparts. Therefore, the best results were achieved not by the N-terminal extension but by the protection of both ends with the d-Leu residue and 4-amidinobenzylamide, which yielded the most stable inhibitor, with an excellent activity and toxicity profile.
authors.affiliation: Département de Chirurgie/Urologie, Faculté de Médecine et Sciences de la Santé, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Ave. Nord Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
authors.forename: Anna
authors.identifier: http://orcid.org/0000-0002-5659-3680
authors.initials: A
authors.lastname: Kwiatkowska
authors.affiliation: Département de Chirurgie/Urologie, Faculté de Médecine et Sciences de la Santé, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Ave. Nord Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Couture
authors.affiliation: Département de Chirurgie/Urologie, Faculté de Médecine et Sciences de la Santé, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Ave. Nord Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Levesque
authors.affiliation: Département de Chirurgie/Urologie, Faculté de Médecine et Sciences de la Santé, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Ave. Nord Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
authors.forename: Kévin
authors.initials: K
authors.lastname: Ly
authors.affiliation: Département de chimie, Faculté des Sciences, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Ave. Nord, Sherbrooke, Québec, J1H 5N4, Canada.
authors.forename: Sophie
authors.initials: S
authors.lastname: Beauchemin
authors.affiliation: Département de Chirurgie/Urologie, Faculté de Médecine et Sciences de la Santé, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Ave. Nord Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
authors.forename: Roxane
authors.initials: R
authors.lastname: Desjardins
authors.affiliation: Département de Chirurgie/Urologie, Faculté de Médecine et Sciences de la Santé, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Ave. Nord Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
authors.forename: Witold
authors.initials: W
authors.lastname: Neugebauer
authors.affiliation: Département de chimie, Faculté des Sciences, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Ave. Nord, Sherbrooke, Québec, J1H 5N4, Canada. Yves.Dory@USherbrooke.ca.
authors.forename: Yves L
authors.initials: YL
authors.lastname: Dory
authors.affiliation: Département de Chirurgie/Urologie, Faculté de Médecine et Sciences de la Santé, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Ave. Nord Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada. Robert.day@Usherbrooke.ca.
authors.forename: Robert
authors.identifier: http://orcid.org/0000-0001-8123-1991
authors.initials: R
authors.lastname: Day
mesh_terms: D061605:Administration, Intravenous; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010455:Peptides; C080654:PCSK6 protein, human; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: PACE4; enzyme inhibitors; proprotein convertases; prostate cancer; structure-activity relationships