N-terminal fatty acid substitution increases the leishmanicidal activity of CA(1-7)M(2-9), a cecropin-melittin hybrid peptide

In order to improve the leishmanicidal activity of the synthetic cecropin A -melittin hybrid peptide CA(1-7)M(2-9) (KWKLFKKIGAVLKVL-NH2), a systematic study of its acylation with saturated linear fatty acids was carried out. A cylation of the N-epsilon-7 lysine residue led to a drastic decrease in lei shmanicidal activity, whereas acylation at lysine 1, in either the alpha or the epsilon NH2 group, increased up to 3 times the activity of the peptide against promastigotes and increased up to 15 times the activity of the pep tide against amastigotes. Leish-manicidal activity increased with the lengt h of the fatty acid chain, reaching a maximum for the lauroyl analogue (12 carbons). According to the fast kinetics, dissipation of membrane potential , and parasite membrane permeability to the nucleic acid binding probe SYTO X green, the lethal mechanism was directly related to plasma membrane perme abilization.