Vinyl sulfones as antiparasitic agents and a structural basis for drug design.
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.
Kerr
Iain D
ID
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158-2550, USA.
Lee
Ji H
JH
Farady
Christopher J
CJ
Marion
Rachael
R
Rickert
Mathias
M
Sajid
Mohammed
M
Pandey
Kailash C
KC
Caffrey
Conor R
CR
Legac
Jennifer
J
Hansell
Elizabeth
E
McKerrow
James H
JH
Craik
Charles S
CS
Rosenthal
Philip J
PJ
Brinen
Linda S
LS
D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry* / Q000627:therapeutic use; D014355:Chagas Disease / Q000188:drug therapy / Q000201:enzymology; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D015195:Drug Design; D007700:Kinetics; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000201:enzymology; D010963:Plasmodium falciparum / Q000201:enzymology*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013450:Sulfones / Q000737:chemistry* / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000201:enzymology*; D014349:Trypanosoma cruzi / Q000201:enzymology*; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000201:enzymology
D000977:Antiparasitic Agents; D011480:Protease Inhibitors; D015800:Protozoan Proteins; D013450:Sulfones; C009873:divinyl sulfone; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi; C443101:falcipain 3; C446033:rhodesain