Peptide-biphenyl hybrids as calpain inhibitors

Abstract

Calpain is a cysteine protease that is activated by Ca2+. The over-activation of calpain, which occurs on increasing Ca2+ concentration, causes a variety of diseases. This paper reports experimental results on the inhibition of calpain I (μ-calpain) by peptide-biphenyl hybrids. We have found that some peptide-biphenyl hybrids, with aromatic amino acids in the peptide chains, inhibit calpain with IC50 values in the nanomolar range. Since the peptide-biphenyl hybrids reported in the present paper do not posses a reactive electrophilic functionality, we hypothesize that they interfere with the activation of calpain by Ca2+, and present experimental and computational results on the binding of peptide-biphenyl hybrids to Ca2+.