title: Identification of new peptide amides as selective cathepsin L inhibitors: the first step towards selective irreversible inhibitors?
abstract: A small library of peptide amides was designed to profile the cathepsin L active site. Within the cathepsin family of cysteine proteases, the first round of selection was on cathepsin L and cathepsin B, and then selected hits were further evaluated for binding to cathepsin K and cathepsin S. Five highly selective sequences with submicromolar affinities towards cathepsin L were identified. An acyloxymethyl ketone warhead was then attached to these sequences. Although these original irreversible inhibitors inactivate cathepsin L, it appears that the nature of the warhead drastically impact the selectivity profile of the resulting covalent inhibitors.
authors.affiliation: Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000 Ljubljana, Slovenia.
authors.forename: Ana
authors.initials: A
authors.lastname: Torkar
authors.forename: Brigita
authors.initials: B
authors.lastname: Lenarčič
authors.forename: Tamara
authors.initials: T
authors.lastname: Lah
authors.forename: Vincent
authors.initials: V
authors.lastname: Dive
authors.forename: Laurent
authors.initials: L
authors.lastname: Devel
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D056668:Cathepsin L / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D054852:Small Molecule Libraries; D056668:Cathepsin L