Assessing Designed Model Membrane-Targeting Peptides Found as Potential Molecular Scaffolds against Cutaneous Leishmaniasis

Recent research has demonstrated therapeutic potential against visceral leishmaniasis, a neglected disease with high prevalence and severity in very populated low- and middle-income regions; however, effective treatments for the cutaneous or mucocutaneous forms remain limited, despite their higher incidence. The negatively charged composition of Leishmania membranes differentiates it from the zwitterionic nature of mammalian cells, providing a basis for selective targeting by cationic peptides. Here, designed peptides (DecP-9, DecP-17, and DecP-18), spanning a broad range of charge and hydrophobicity, were evaluated and displayed distinct antileishmanial activity and selectivity, including effects on amastigote-infected macrophages. Biophysical studies revealed their interaction profiles: (i) DecP-9, with helical structure and strong lytic activity, showed high activity but low selectivity; (ii) DecP-18, enriched in β-stranded structures, exhibited limited partitioning, low lytic activity, and membrane translocation, resulting in low antiparasitic activity and high mammalian cell survival; (iii) DecP-17 displayed intermediate behavior, reducing intracellular amastigotes without significant cytotoxicity. Although there is a scenario of valued and challenging features in the development of therapeutic peptides, it seems that to find drug peptides that will cutaneously act, but whose ultimate target is the amastigote form contained inside the macrophage, a deeper understanding of membrane processes is required.