New analogues of the endogenous heptapeptide VV-hemorphin-5 (valorphin) synthesised by amino acid replacement allow for tailoring the peptide activity in vivo. Investigation of hemorphin-induced alterations of lipid bilayers' physicochemical parameters unravels membrane-mediated mechanisms of interaction with cells and subcellular structures. We studied the effect of modified valorphins with nociceptive activity on the structure, mechanical and electrical properties of lipid membrane models. Lower bending rigidity and higher specific capacitance of phosphatidylcholine bilayers were found in the presence of VV-hemorphin-5 analogues. Peptide partition constants for the transfer from the aqueous solution into the membrane were determined by isothermal titration calorimetry. It was found that the inclusion of non-proteinogenic acids with different number of methylene groups lead to alterations of hemorphin-membrane binding. The highest membrane affinity was obtained for a hemorphin derivative with dose-dependent variable effects on visceral nociception in mice. The valorphin analogue with the most pronounced anti-nociceptive effect in vivo induced the highest dipole and zeta potential change without significantly affecting the lipid packing at glycerol level in phosphatidylcholine bilayers.
Keywords: Bending rigidity; Dipole potential; Electrical capacitance; Lipid bilayer; Lipid packing; VV-hemorphin-5.
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