Development of novel peptide-based Michael acceptors targeting rhodesain and falcipain-2 for the treatment of neglected tropical siseases (NTDs)
This paper describes the development of a class of peptide-based inhibitors as novel antitrypanosomal and antimalarial agents. The inhibitors are based on a characteristic peptide sequence for the inhibition of the cysteine proteases rhodesain of Trypanosoma brucei rhodesiense and falcipain-2 of Pla...
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| Hauptverfasser: | , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
August 1, 2017
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| In: |
Journal of medicinal chemistry
Year: 2017, Jahrgang: 60, Heft: 16, Pages: 6911-6923 |
| ISSN: | 1520-4804 |
| DOI: | 10.1021/acs.jmedchem.7b00405 |
| Online-Zugang: | Verlag, Volltext: http://dx.doi.org/10.1021/acs.jmedchem.7b00405 Verlag, Volltext: https://doi.org/10.1021/acs.jmedchem.7b00405 
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| Verfasserangaben: | Santo Previti, Roberta Ettari, Sandro Cosconati, Giorgio Amendola, Khawla Chouchene, Annika Wagner, Ute A. Hellmich, Kathrin Ulrich, R. Luise Krauth-Siegel, Peter R. Wich, Ira Schmid, Tanja Schirmeister, Jiri Gut, Philip J. Rosenthal, Silvana Grasso, Maria Zappalà |
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| 245 | 1 | 0 | |a Development of novel peptide-based Michael acceptors targeting rhodesain and falcipain-2 for the treatment of neglected tropical siseases (NTDs) |c Santo Previti, Roberta Ettari, Sandro Cosconati, Giorgio Amendola, Khawla Chouchene, Annika Wagner, Ute A. Hellmich, Kathrin Ulrich, R. Luise Krauth-Siegel, Peter R. Wich, Ira Schmid, Tanja Schirmeister, Jiri Gut, Philip J. Rosenthal, Silvana Grasso, Maria Zappalà |
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| 520 | |a This paper describes the development of a class of peptide-based inhibitors as novel antitrypanosomal and antimalarial agents. The inhibitors are based on a characteristic peptide sequence for the inhibition of the cysteine proteases rhodesain of Trypanosoma brucei rhodesiense and falcipain-2 of Plasmodium falciparum. We exploited the reactivity of novel unsaturated electrophilic functions such as vinyl-sulfones, -ketones, -esters, and -nitriles. The Michael acceptors inhibited both rhodesain and falcipain-2, at nanomolar and micromolar levels, respectively. In particular, the vinyl ketone 3b has emerged as a potent rhodesain inhibitor (k2nd = 67 × 106 M-1 min-1), endowed with a picomolar binding affinity (Ki = 38 pM), coupled with a single-digit micromolar activity against Trypanosoma brucei brucei (EC50 = 2.97 μM), thus being considered as a novel lead compound for the discovery of novel effective antitrypanosomal agents. | ||
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