Rational Design of Calpain Inhibitors Based on Calpastatin Peptidomimetics

作者: Kristin E. Low , Spencer Ler , Kevin J. Chen , Robert L. Campbell , Jennifer L. Hickey

DOI: 10.1021/ACS.JMEDCHEM.6B00267

关键词:

摘要: Our previously reported structures of calpain bound to its endogenous inhibitor calpastatin have motivated the use aziridine aldehyde-mediated peptide macrocyclization toward design cyclic peptides and peptidomimetics as inhibitors. Inspired by nature’s hint that a β-turn loop within forms broad interaction around calpain’s active site cysteine, we constructed tested library 45 peptidic compounds based on this sequence. Four molecules shown reproducibly low micromolar inhibition calpain-2. Further systematic sequence changes led development probes displayed increased potency specificity against over other cysteine proteases. Calculated Ki values were in range, rivaling peptidomimetic inhibitors presenting an improved selectivity profile therapeutically relevant Competitive mixed calpain-2 was observed, allosteric inh...

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