title: Toward very potent, non-covalent organophosphonate inhibitors of cathepsin C and related enzymes by 2-amino-1-hydroxy-alkanephosphonates dipeptides.
abstract: Cathepsins play an important role in several human disorders and therefore the design and synthesis of their inhibitors attracts considerable interest in current medicinal chemistry approaches. Due to the presence of a strong sulphydryl nucleophile in the active center of the cysteine type cathepsins, most strategies to date have yielded covalent inhibitors. Here we present a series of non-covalent β-amino-α-hydroxyalkanephosphonate dipeptidic inhibitors of cathepsin C, ranking amongst the best low-molecular weight inhibitors of this enzyme. Their binding modes determined by molecular modelling indicate that the hydroxymethyl fragment of the molecule, not the phosphonate moiety, acts as a transition state analogue of peptide bond hydrolysis. These dipeptide mimetics appear also to be potent inhibitors of other cysteine proteases such as papain, cathepsin B and cathepsin K, thus providing new leading structures for these medicinally important enzymes.
authors.affiliation: Department of Bioorganic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, Wybrzeże Wyspiańskiego 27, Wrocław, Poland. marcin.drag@pwr.wroc.pl
authors.forename: Marcin
authors.initials: M
authors.lastname: Drąg
authors.forename: Ewa
authors.initials: E
authors.lastname: Wieczerzak
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Pawełczak
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Berlicki
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Grzonka
authors.forename: Paweł
authors.initials: P
authors.lastname: Kafarski
mesh_terms: D000588:Amines / Q000737:chemistry / Q000494:pharmacology; D020789:Cathepsin C / Q000037:antagonists & inhibitors; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006880:Hydroxy Acids / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D018716:Molecular Mimicry; D010755:Organophosphates / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000588:Amines; D004151:Dipeptides; D004791:Enzyme Inhibitors; D006880:Hydroxy Acids; D010755:Organophosphates; D020789:Cathepsin C