Rational Design of Calpain Inhibitors Based on Calpastatin Peptidomimetics.

Four cyclic peptidomimetic compounds exhibited low micromolar inhibition of calpain-2, with improved potency and selectivity over other cysteine proteases. The study identified both competitive and mixed inhibition mechanisms, including an allosteric site for noncompetitive inhibition.

A library of 45 cyclic peptide compounds based on a β-turn loop sequence from calpastatin was synthesized using aziridine aldehyde-mediated macrocyclization. These compounds were tested for inhibitory activity against calpain-2 and other cysteine proteases, and inhibition constants (Ki) were calculated to assess potency and selectivity.

Calpain enzymes are implicated in many diseases, so developing selective inhibitors can lead to targeted therapies with fewer side effects. This study advances peptide-based drug design by providing potent and selective calpain inhibitors.

The study does not specify in vivo efficacy or toxicity data, and the exact clinical relevance of these inhibitors remains to be established. The evidence strength and study type were not clearly defined.