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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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Bibliographic Details
Main Authors: Previti, Santo (Author) , Ulrich, Kathrin (Author) , Krauth-Siegel, Renate (Author)
Format: Article (Journal)
Language:English
Published: August 1, 2017
In: Journal of medicinal chemistry
Year: 2017, Volume: 60, Issue: 16, Pages: 6911-6923
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.7b00405
Online Access: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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Author Notes: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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Summary: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.
Item Description:Gesehen am 25.09.2018
Physical Description:Online Resource
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.7b00405

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