title: On-bead screening of a combinatorial fumaric acid derived peptide library yields antiplasmodial cysteine protease inhibitors with unusual peptide sequences.
abstract: A new class of cysteine protease inhibitors based on fumaric acid derived oligopeptides was successfully identified from a high-throughput screening of a solid-phase bound combinatorial library. As target enzymes falcipain and rhodesain were used, which play important roles in the life cycles of the parasites which cause malaria (Plasmodium falciparum) and African sleeping sickness (Trypanosoma brucei rhodesiense). The best inhibitors with unusual amino acid sequences not reported before for this type of enzyme were also fully analyzed in detail in solution. K(i) values in the lower micromolar and even nanomolar region were found. Some inhibitors are even active against plasmodia and show good selectivity relative to other enzymes. Also the mechanism of action was studied and could be shown to be irreversible inhibition.
authors.affiliation: Institute of Organic Chemistry, University of Duisburg-Essen, Universitatstrasse 7, 45141 Essen, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Machon
authors.forename: Christian
authors.initials: C
authors.lastname: Büchold
authors.forename: Martin
authors.initials: M
authors.lastname: Stempka
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
authors.forename: Christoph
authors.initials: C
authors.lastname: Gelhaus
authors.forename: Matthias
authors.initials: M
authors.lastname: Leippe
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Caroline
authors.initials: C
authors.lastname: Kisker
authors.forename: Matthias
authors.initials: M
authors.lastname: Leyh
authors.forename: Carsten
authors.initials: C
authors.lastname: Schmuck
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D056668:Cathepsin L; D002403:Cathepsins / Q000737:chemistry; D002417:Cattle; D020650:Combinatorial Chemistry Techniques; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003958:Diamide / Q000737:chemistry; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005650:Fumarates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D019151:Peptide Library; D010963:Plasmodium falciparum / Q000201:enzymology*
chemical_list: D000981:Antiprotozoal Agents; D015853:Cysteine Proteinase Inhibitors; D005650:Fumarates; D019151:Peptide Library; D003958:Diamide; C032005:fumaric acid; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C416224:falcipain 2; C446033:rhodesain; C534281:CTSL protein, human; D056668:Cathepsin L