Potent and selective inhibition of cysteine proteases from Plasmodium falciparum and Trypanosoma brucei

Veronika Ehmke; Cornelia Heindl; Matthias Rottmann; Céline Freymond; W Bernd Schweizer; Reto Brun; August Stich; Tanja Schirmeister; François Diederich

doi:10.1002/cmdc.201000449

Potent and selective inhibition of cysteine proteases from Plasmodium falciparum and Trypanosoma brucei

ChemMedChem. 2011 Feb 7;6(2):273-8. doi: 10.1002/cmdc.201000449. Epub 2010 Nov 25.

Authors

Veronika Ehmke¹, Cornelia Heindl, Matthias Rottmann, Céline Freymond, W Bernd Schweizer, Reto Brun, August Stich, Tanja Schirmeister, François Diederich

Affiliation

¹ Laboratory of Organic Chemistry, ETH Zürich, Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland.

Abstract

Treating tropical diseases: Structure‐based design afforded highly active triazine nitrile inhibitors of the protozoan cysteine proteases falcipain‐2 and rhodesain. Optimization of the occupancy of the S1, S2, and S3 pockets of these enzymes yielded inhibitory constants in the low nanomolar activity range. The new ligands are selective against other related proteases and exhibit in vitro activities against the protozoan parasites.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Crystallography, X-Ray
Cysteine Proteases / chemistry
Cysteine Proteases / metabolism*
Cysteine Proteinase Inhibitors / pharmacology*
Models, Molecular
Plasmodium falciparum / enzymology*
Trypanosoma brucei brucei / enzymology*

Substances

Cysteine Proteinase Inhibitors
Cysteine Proteases