title: Evaluation of dipeptide nitriles as inhibitors of rhodesain, a major cysteine protease of Trypanosoma brucei.
abstract: A series of dipeptide nitriles known as inhibitors of mammalian cathepsins were evaluated for inhibition of rhodesain, the cathepsin L-like protease of Trypanosoma brucei. Compound 35 consisting of a Leu residue fitting into the S2 pocket and a triarylic moiety consisting of thiophene, a 1,2,4-oxadiazole and a phenyl ring fitting into the S3 pocket, and compound 33 with a 3-bromo-Phe residue (S2) and a biphenyl fragment (S3) were found to inhibit rhodesain in the single-digit nanomolar range. The observed steep structure-activity relationship could be explained by covalent docking simulations. With their high selectivity indices (ca. 200) and the good antitrypanosomal activity (8μM) the compounds represent promising starting points for new rhodesain inhibitors.
authors.affiliation: Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University, Staudingerweg 5, 55128 Mainz, Germany. Electronic address: schirmei@uni-mainz.de.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Schmitz
authors.affiliation: Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University, Staudingerweg 5, 55128 Mainz, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Jung
authors.affiliation: Biochemie-Zentrum der Universität Heidelberg (BZH), Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Schmenger
authors.affiliation: Biochemie-Zentrum der Universität Heidelberg (BZH), Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
authors.forename: R Luise
authors.initials: RL
authors.lastname: Krauth-Siegel
authors.affiliation: Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology
chemical_list: D000995:Antitubercular Agents; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D009570:Nitriles; D003546:Cysteine Endopeptidases; C446033:rhodesain
keywords: Cysteine protease; Dipeptide nitrile; Inhibitor; Rhodesain; Trypanosoma