title: Positional Scanning Identifies the Molecular Determinants of a High Affinity Multi-Leucine Inhibitor for Furin and PACE4.
abstract: The proprotein convertase family of enzymes includes seven endoproteases with significant redundancy in their cleavage activity. We previously described the peptide Ac-LLLLRVK-Amba that displays potent inhibitory effects on both PACE4 and prostate cancer cell lines proliferation. Herein, the molecular determinants for PACE4 and furin inhibition were investigated by positional scanning using peptide libraries that substituted its leucine core with each natural amino acid. We determined that the incorporation of basic amino acids led to analogues with improved inhibitory potency toward both enzymes, whereas negatively charged residues significantly reduced it. All the remaining amino acids were in general well tolerated, with the exemption of the P6 position. However, not all of the potent PACE4 inhibitors displayed antiproliferative activity. The best analogues were obtained by the incorporation of the Ile residue at the P5 and P6 positions. These substitutions led to inhibitors with increased PACE4 selectivity and potent antiproliferative effects.
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, University of Gdańsk , 80-308 Gdańsk, Poland.
authors.forename: Izabela
authors.initials: I
authors.lastname: Małuch
authors.affiliation: Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke , 3001 12e Avenue Nord, Sherbrooke J1H 5N4, Canada.|Département de Chirurgie/Urologie, Centre Hospitalier Université de Sherbrooke , 3001 12e Avenue Nord, J1H 5N4 Sherbrooke, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Levesque
authors.affiliation: Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke , 3001 12e Avenue Nord, Sherbrooke J1H 5N4, Canada.|Département de Chirurgie/Urologie, Centre Hospitalier Université de Sherbrooke , 3001 12e Avenue Nord, J1H 5N4 Sherbrooke, Canada.
authors.forename: Anna
authors.identifier: 0000-0002-5659-3680
authors.initials: A
authors.lastname: Kwiatkowska
authors.affiliation: Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke , 3001 12e Avenue Nord, Sherbrooke J1H 5N4, Canada.|Département de Chirurgie/Urologie, Centre Hospitalier Université de Sherbrooke , 3001 12e Avenue Nord, J1H 5N4 Sherbrooke, Canada.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Couture
authors.affiliation: Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke , 3001 12e Avenue Nord, Sherbrooke J1H 5N4, Canada.|Département de Chirurgie/Urologie, Centre Hospitalier Université de Sherbrooke , 3001 12e Avenue Nord, J1H 5N4 Sherbrooke, Canada.
authors.forename: Kévin
authors.initials: K
authors.lastname: Ly
authors.affiliation: Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke , 3001 12e Avenue Nord, Sherbrooke J1H 5N4, Canada.|Département de Chirurgie/Urologie, Centre Hospitalier Université de Sherbrooke , 3001 12e Avenue Nord, J1H 5N4 Sherbrooke, Canada.
authors.forename: Roxane
authors.initials: R
authors.lastname: Desjardins
authors.affiliation: Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke , 3001 12e Avenue Nord, Sherbrooke J1H 5N4, Canada.
authors.forename: Witold A
authors.initials: WA
authors.lastname: Neugebauer
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry, University of Gdańsk , 80-308 Gdańsk, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Prahl
authors.affiliation: Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke , 3001 12e Avenue Nord, Sherbrooke J1H 5N4, Canada.|Département de Chirurgie/Urologie, Centre Hospitalier Université de Sherbrooke , 3001 12e Avenue Nord, J1H 5N4 Sherbrooke, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Day
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D045683:Furin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019151:Peptide Library; D010455:Peptides; C080654:PCSK6 protein, human; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D045683:Furin