Rational Design of Calpain Inhibitors Based on Calpastatin Peptidomimetics.

Autor:	Low KE; Department of Biomedical and Molecular Sciences, Queen's University , Kingston, Ontario K7L 3N6, Canada., Ler S; Department of Chemistry, University of Toronto , Toronto, Ontario M5S 3H6, Canada., Chen KJ; Department of Biomedical and Molecular Sciences, Queen's University , Kingston, Ontario K7L 3N6, Canada., Campbell RL; Department of Biomedical and Molecular Sciences, Queen's University , Kingston, Ontario K7L 3N6, Canada., Hickey JL; Encycle Therapeutics Inc. , 101 College Street, Suite 314, Toronto, Ontario M5G 1L7, Canada., Tan J; Department of Chemistry, University of Toronto , Toronto, Ontario M5S 3H6, Canada., Scully CC; Department of Chemistry, University of Toronto , Toronto, Ontario M5S 3H6, Canada., Davies PL; Department of Biomedical and Molecular Sciences, Queen's University , Kingston, Ontario K7L 3N6, Canada., Yudin AK; Department of Chemistry, University of Toronto , Toronto, Ontario M5S 3H6, Canada., Zaretsky S; Department of Chemistry, University of Toronto , Toronto, Ontario M5S 3H6, Canada.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2016 Jun 09; Vol. 59 (11), pp. 5403-15. Date of Electronic Publication: 2016 May 18.
DOI:	10.1021/acs.jmedchem.6b00267
Abstrakt:	Our previously reported structures of calpain bound to its endogenous inhibitor calpastatin have motivated the use of aziridine aldehyde-mediated peptide macrocyclization toward the design of cyclic peptides and peptidomimetics as calpain inhibitors. Inspired by nature's hint that a β-turn loop within calpastatin forms a broad interaction around calpain's active site cysteine, we have constructed and tested a library of 45 peptidic compounds based on this loop sequence. Four molecules have shown reproducibly low micromolar inhibition of calpain-2. Further systematic sequence changes led to the development of probes that displayed increased potency and specificity of inhibition against calpain over other cysteine proteases. Calculated Ki values were in the low micromolar range, rivaling other peptidomimetic calpain inhibitors and presenting an improved selectivity profile against other therapeutically relevant proteases. Competitive and mixed inhibition against calpain-2 was observed, and an allosteric inhibition site on the enzyme was identified for a noncompetitive inhibitor.
Databáze:	MEDLINE
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