title: Dipeptidyl Enoates As Potent Rhodesain Inhibitors That Display a Dual Mode of Action.
abstract: Dipeptidyl enoates were prepared through a high-yielding two-step synthetic route. They have a dipeptidic structure with a 4-oxoenoate moiety as a warhead with multiple reactive sites. Dipeptidyl enoates were screened against rhodesain and human cathepsins B and L, and were found to be potent and selective inhibitors of rhodesain. Among them (S,E)-ethyl 5-((S)-2-{[(benzyloxy)carbonyl]amino}-3-phenylpropanamido)-7-methyl-4-oxooct-2-enoate (6) was the most potent, with an IC50 value of 16.4 nM and kinact /Ki =1.6×10(6)  M(-1)  s(-1) against rhodesain. These dipeptidyl enoates display a reversible mode of inhibition at very low concentrations and an irreversible mode at higher concentrations. Inhibition kinetics data, supported by docking studies, suggest a dual mode of action via attack of cysteine thiolate at two reactive positions.
authors.affiliation: Departament de Química Inorgànica i Orgànica, Universitat Jaume I, 12080 Castelló (Spain).
authors.forename: Santiago
authors.initials: S
authors.lastname: Royo
authors.affiliation: Departament de Química Inorgànica i Orgànica, Universitat Jaume I, 12080 Castelló (Spain).
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodríguez
authors.affiliation: Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55099 Mainz (Germany).
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
authors.affiliation: Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55099 Mainz (Germany).
authors.forename: Jochen
authors.initials: J
authors.lastname: Kesselring
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051 Basel (Switzerland).|University of Basel, Petersplatz 1, 4003 Basel (Switzerland).
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Departament de Química Inorgànica i Orgànica, Universitat Jaume I, 12080 Castelló (Spain). fgonzale@uji.es.
authors.forename: Florenci V
authors.initials: FV
authors.lastname: González
mesh_terms: D002401:Cathepsin B / Q000037:antagonists & inhibitors; D056668:Cathepsin L / Q000037:antagonists & inhibitors; D060326:Chemistry Techniques, Synthetic; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy / Q000379:methods; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D014344:Trypanocidal Agents; C000608410:ethyl 5-(2-(((benzyloxy)carbonyl)amino)-3-phenylpropanamido)-7-methyl-4-oxooct-2-enoate; D003546:Cysteine Endopeptidases; C446033:rhodesain; C533912:CTSB protein, human; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L
keywords: dipeptidyl enoates; inhibitors; rhodesain; sleeping sickness; trypanosomiasis