title: Inhibition of cysteine proteases by peptides containing aziridine-2,3-dicarboxylic acid building blocks.
abstract: Mammalian cysteine proteases of the papain superfamily are interesting targets for the development of new drugs against diseases connected to abnormal degradation of muscle or bone proteins. The high nucleophilicity of the active site of these proteases as well as the characteristics of the well-known epoxysuccinic acid derived cysteine protease inhibitors provided a basis for the design of new types of selective and irreversible inhibitors for these enzymes. We designed and synthesized a novel class of peptidic cysteine protease inhibitors containing aziridine-2,3-dicarboxylic acid as electrophilic amino acid. Three types of aziridinyl peptides that differ in the position of the aziridine building block within the peptide chain have been synthesized and tested as inhibitors of several cysteine proteases. Remarkable differences could be observed between the three types of inhibitors concerning their activity, stereospecificity, pH dependency of inhibition, and selectivity between different cysteine proteases, respectively, indicating that different binding modes of the three types of inhibitors in respect to their orientation in the S and S' binding sites of the enzymes may be present.
authors.affiliation: Department of Pharmaceutical Chemistry, Albert-Ludwigs University of Freiburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Schirmeister
mesh_terms: D001388:Aziridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001847:Bone Diseases / Q000188:drug therapy; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D003998:Dicarboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D009135:Muscular Diseases / Q000188:drug therapy; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010206:Papain / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D001388:Aziridines; D015853:Cysteine Proteinase Inhibitors; D003998:Dicarboxylic Acids; D009842:Oligopeptides; D002403:Cathepsins; D010206:Papain