title: Vinyl sulfones as antiparasitic agents and a structural basis for drug design.
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.
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158-2550, USA.
authors.forename: Iain D
authors.initials: ID
authors.lastname: Kerr
authors.forename: Ji H
authors.initials: JH
authors.lastname: Lee
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Farady
authors.forename: Rachael
authors.initials: R
authors.lastname: Marion
authors.forename: Mathias
authors.initials: M
authors.lastname: Rickert
authors.forename: Mohammed
authors.initials: M
authors.lastname: Sajid
authors.forename: Kailash C
authors.initials: KC
authors.lastname: Pandey
authors.forename: Conor R
authors.initials: CR
authors.lastname: Caffrey
authors.forename: Jennifer
authors.initials: J
authors.lastname: Legac
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hansell
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.forename: Charles S
authors.initials: CS
authors.lastname: Craik
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Linda S
authors.initials: LS
authors.lastname: Brinen
mesh_terms: 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
chemical_list: 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