Dipeptidyl Nitroalkenes as Potent Reversible Inhibitors of Cysteine Proteases Rhodesain and Cruzain

Antonio Latorre; Tanja Schirmeister; Jochen Kesselring; Sascha Jung; Patrick Johé; Ute A Hellmich; Anna Heilos; Bernd Engels; R Luise Krauth-Siegel; Natalie Dirdjaja; Lledó Bou-Iserte; Santiago Rodríguez; Florenci V González

doi:10.1021/acsmedchemlett.6b00276

Dipeptidyl Nitroalkenes as Potent Reversible Inhibitors of Cysteine Proteases Rhodesain and Cruzain

ACS Med Chem Lett. 2016 Sep 21;7(12):1073-1076. doi: 10.1021/acsmedchemlett.6b00276. eCollection 2016 Dec 8.

Affiliations

¹ Departament de Química Inorgànica i Orgànica, Universitat Jaume I , 12080 Castelló, Spain.
² Institute of Pharmacy and Biochemistry, University of Mainz , Staudinger Weg 5, 55099 Mainz, Germany.
³ Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55099 Mainz, Germany; Institute of Pharmacy and Biochemistry, University of Mainz, Johann-Joachim Becherweg 30, 55128 Mainz, Germany; Center of Biomolecular Magnetic Resonance (BMRZ), Goethe University, 60323 Frankfurt, Germany.
⁴ Institute of Phys. and Theor. Chemistry, University of Würzburg , Emil-Fischer-Straße 42, 97074 Würzburg, Germany.
⁵ Biochemie-Zentrum Heidelberg (BZH), Universität Heidelberg , Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.

Abstract

Dipeptidyl nitroalkenes are potent reversible inhibitors of cysteine proteases. Inhibitor 11 resulted to be the most potent one with K_i values of 0.49 and 0.44 nM against rhodesain and cruzain, respectively. According to enzymatic dilution and dialysis experiments, as well as computational and NMR studies, dipeptidyl nitroalkenes are tightly binding covalent reversible inhibitors.

Keywords: Chagas’ disease; Rhodesain; cruzain; inhibitors; sleeping sickness.