Development of Novel Benzodiazepine-Based Peptidomimetics as Inhibitors of Rhodesain from Trypanosoma brucei rhodesiense |
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Authors: | Dr Carla Di Chio Dr Santo Previti Dr Giorgio Amendola Prof Sandro Cosconati Prof Tanja Schirmeister Prof Maria Zappalà Prof Roberta Ettari |
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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. Institute of Pharmaceutical and Biomedical Sciences, University of Mainz, Staudingerweg 5, 55128 Mainz, Germany |
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Abstract: | Starting from the reversible rhodesain inhibitors 1 a – c , which have Ki values towards the target protease in the low-micromolar range, we have designed a series of peptidomimetics, 2 a – g , that contain a benzodiazepine scaffold as a β-turn mimetic; they are characterized by a specific peptide sequence for the inhibition of rhodesain. Considering that irreversible inhibition is strongly desirable in the case of a parasitic target, a vinyl ester moiety acting as Michael-acceptor was introduced as the warhead; this portion was functionalized in order to evaluate the size of corresponding enzyme pocket that could accommodate this substituent. With this investigation, we identified an irreversible rhodesain inhibitor (i. e., 2 g ) with a k2nd value of 90 000 M−1 min−1 that showed antitrypanosomal activity in the low-micromolar range (EC50=1.25 μM), this may be considered a promising lead compound in the drug-discovery process for treating human African trypanosomiasis (HAT). |
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Keywords: | benzodiazepine scaffold human African trypanosomiasis Michael acceptors rhodesain Trypanosoma brucei peptidomimetics |
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