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ACS Med Chem Lett. 2015 Dec 15;7(1):77-82. doi: 10.1021/acsmedchemlett.5b00336. eCollection 2016 Jan 14.

Synthesis and Evaluation of Oxyguanidine Analogues of the Cysteine Protease Inhibitor WRR-483 against Cruzain.

Author information

1
Department of Chemistry, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
2
Department of Pathology and Sandler Center for Drug Discovery, University of California-San Francisco , 1700 Fourth Street, San Francisco, California 94158-2250, United States.
3
Small Molecule Discovery Center, University of California-San Francisco , 1700 Fourth Street, San Francisco, California 94158-2250, United States.
4
Department of Molecular Therapeutics, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
5
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California-San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.
6
Department of Pathology, University of California-San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.
7
Departments of Pathology and Medicine, University of California-San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.

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.

KEYWORDS:

Chagas’ disease; X-ray crystallography; cysteine protease inhibitor; kinetics; noncovalent inhibitor; vinyl sulfone

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