Peptidase-resistant peptide inhibitors of myosin light chain kinase

Myosin light chain kinase (MLCK) is a key regulator of various forms of cellular mobility, in particular, endothelial and epithelial permeability. The membrane-penetrative peptide (H-RKKYKYRRK-NH(2), L-PIK) is one of the potential MLCK inhibitors for use in humans. Five analogs of L-PIK were synthesized by the solid phase method of peptide synthesis using Fmoc technology. According to (1)H NMR, these analogs exhibited increased stability towards degradation in blood plasma. One of the synthesized peptides, L-[MeArg(1)]PIK, inhibited MLCK activity in vitro, and the inhibition efficacy of L-[MeArg(1)]PIK was equal to that of L-PIK. The inhibitory effect of the other analogs was lower than that of L-PIK. The L-PIK analog that consisted of D-amino acids was the least active. Thus, we demonstrated the possibility of creating an effective peptide inhibitor of MLCK with increased stability against biodegradation. Such a peptide inhibitor is a promising compound for further pharmacological studies.