Abstract
Cysteine proteases of the papain superfamily are implicated in a number of cellular processes and are important virulence factors in the pathogenesis of parasitic disease. These enzymes have therefore emerged as promising targets for antiparasitic drugs. We report the crystal structures of three major parasite cysteine proteases, cruzain, falcipain-3, and the first reported structure of rhodesain, in complex with a class of potent, small molecule, cysteine protease inhibitors, the vinyl sulfones. These data, in conjunction with comparative inhibition kinetics, provide insight into the molecular mechanisms that drive cysteine protease inhibition by vinyl sulfones, the binding specificity of these important proteases and the potential of vinyl sulfones as antiparasitic drugs.
Highlights
T. cruzi, T. brucei, and P. falciparum produce an array of potential target enzymes implicated in pathogenesis and host cell invasion, including a number of essential and closely related papain-family cysteine proteases [5, 6]
In P. falciparum, the papain-family cysteine proteases falcipain-2 (FP-2)6 and falcipain-3 (FP-3) are known to catalyze the proteolysis of host hemoglobin, a process that is essential for the development of erythrocytic parasites [15,16,17]
The structure of the FP-31⁄7K11017 complex crystallized with four copies of the complex in the asymmetric unit and was determined to 2.42 Å
Summary
Refinement Rfree/Rfactor (%) Average B-factor (Å2) r.m.s.d. Bond length (Å) Bond angle Ramachandran plotb Favored (%) Allowed (%) Outliers (%) PDB ID. These results help validate the vinyl sulfones as a class of antiparasitic drugs and provide structural insights to facilitate the design or modification of other small molecule inhibitor scaffolds
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