title: Synthesis and Evaluation of Oxyguanidine Analogues of the Cysteine Protease Inhibitor WRR-483 against Cruzain.
abstract: A series of oxyguanidine analogues of the cysteine protease inhibitor WRR-483 were synthesized and evaluated against cruzain, the major cysteine protease of the protozoan parasite Trypanosoma cruzi. Kinetic analyses of these analogues indicated that they have comparable potency to previously prepared vinyl sulfone cruzain inhibitors. Co-crystal structures of the oxyguanidine analogues WRR-666 (4) and WRR-669 (7) bound to cruzain demonstrated different binding interactions with the cysteine protease, depending on the aryl moiety of the P1' inhibitor subunit. Specifically, these data demonstrate that WRR-669 is bound noncovalently in the crystal structure. This represents a rare example of noncovalent inhibition of a cysteine protease by a vinyl sulfone inhibitor.
authors.affiliation: Department of Chemistry, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Jones
authors.affiliation: Department of Pathology and Sandler Center for Drug Discovery, University of California-San Francisco , 1700 Fourth Street, San Francisco, California 94158-2250, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Tochowicz
authors.affiliation: Small Molecule Discovery Center, University of California-San Francisco , 1700 Fourth Street, San Francisco, California 94158-2250, United States.
authors.forename: Yinyan
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California-San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.
authors.forename: Laura-Isobel
authors.initials: LI
authors.lastname: McCall
authors.affiliation: Department of Pathology, University of California-San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.
authors.forename: Ken
authors.initials: K
authors.lastname: Hirata
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California-San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.
authors.forename: Jair L
authors.initials: JL
authors.lastname: Siqueira-Neto
authors.affiliation: Departments of Pathology and Medicine, University of California-San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Reed
authors.affiliation: Department of Pathology and Sandler Center for Drug Discovery, University of California-San Francisco , 1700 Fourth Street, San Francisco, California 94158-2250, United States.
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.affiliation: Department of Chemistry, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
keywords: Chagas’ disease; X-ray crystallography; cysteine protease inhibitor; kinetics; noncovalent inhibitor; vinyl sulfone
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