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Crystal structure analysis of cruzain bound to the no-covalent analog of WRR-483 (WRR-669)Crystal structure analysis of cruzain bound to the no-covalent analog of WRR-483 (WRR-669)
Structural highlights
FunctionCYSP_TRYCR Hydrolyzes chromogenic peptides at the carboxyl Arg or Lys; requires at least one more amino acid, preferably Arg, Phe, Val or Leu, between the terminal Arg or Lys and the amino-blocking group. The cysteine protease may play an important role in the development and differentiation of the parasites at several stages of their life cycle. Publication Abstract from PubMedA 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. Synthesis and Evaluation of Oxyguanidine Analogues of the Cysteine Protease Inhibitor WRR-483 against Cruzain.,Jones BD, Tochowicz A, Tang Y, Cameron MD, McCall LI, Hirata K, Siqueira-Neto JL, Reed SL, McKerrow JH, Roush WR ACS Med Chem Lett. 2015 Dec 15;7(1):77-82. doi: 10.1021/acsmedchemlett.5b00336., eCollection 2016 Jan 14. PMID:26819670[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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