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Peptidyl Vinyl Ketone Irreversible Inhibitors of Rhodesain: Modifications of the P2 Fragment |
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| Authors: | Dr Santina Maiorana Prof Roberta Ettari Dr Santo Previti Dr Giorgio Amendola Dr Annika Wagner Prof Sandro Cosconati Prof Ute A Hellmich Prof Tanja Schirmeister Prof Maria Zappalà |
| Affiliation: | 1. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Annunziata, 98168 Messina, Italy;2. DiSTABiF, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100 Caserta, Italy;3. Department Centre for Biomolecular Magnetic Resonance (BMRZ), Max von Laue Str. 9, 60438 Frankfurt, Germany
Department of Chemistry Section Biochemistry, University of Mainz, Johann-Joachim-Becherweg 30, 55128 Mainz, Germany;4. Institute of Pharmaceutical and Biomedical Sciences, University of Mainz, Staudingerweg 5, 55128 Mainz, Germany |
| Abstract: | In this paper, we report the design, synthesis and biological investigation of a series of peptidyl vinyl ketones obtained by modifying the P2 fragment of previously reported highly potent inhibitors of rhodesain, the main cysteine protease of Trypanosoma brucei rhodesiense. Investigation of the structure–activity relationship led us to identify new rhodesain inhibitors endowed with an improved selectivity profile (a selectivity index of up to 22 000 towards the target enzyme), and/or an improved antitrypanosomal activity in the sub-micromolar range. |
| Keywords: | cathepsin L Michael acceptors rhodesain selectivity Trypanosoma brucei |