Membrane targeting peptides toward antileishmanial activity: Design, structural determination and mechanism of interaction

Autor(es)

Martins, Danubia Batista ; Vieira, Maira Ramos ; Fadel, Valmir ; Camargo Santana, Viviane Aparecida ; Rodrigues Guerr, Mirian Elisa ; Lima, Marta Lopes ; Tempone, Andre G. ; dos Santos Cabrera, Marcia Perez

• Tipo de documento: Artigo Científico
• Fonte: BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS; v. 1861, n. 11, p. 11-pg., 2017-11-01.

Resumo

Background: Leishmaniasis threatens poor areas population worldwide, requiring new drugs less prone to resistance development. Antimicrobial peptides with antileishmanial activity are considered among fulfilling alternatives, but not much is known about the mode of action of membrane-targeting peptides, considering promastigote and infected macrophage membranes. In a previous work, structural features of very active known peptides were prospected using molecular dynamics simulations. Methods: Combining sequences of these peptides, analogs were designed. The structure of analog DecP-11 was validated by NMR. In vitro bioassays determined the peptide cytotoxicity toward mammalian cells, IC50 values on promastigotes and amastigotes, and membranolytic activity compared to Decoralin, one of the parent peptides. With biophysical methods, the mechanism of interaction with membrane mimetic systems was investigated. Results: The designed peptide exhibits potent cytolytic and membrane permeabilizing activities, and decreased antileishmanial activity compared to the parent peptide. Interactions with lipid bilayers mimicking those of promastigotes, infected macrophage and mammalian cells showed that these peptides strongly bind to vesicles with intense lytic activity at low concentrations. Additionally, circular dichroism and light scattering experiments showed changes in the secondary structure of peptides and in vesicle size, depending on vesicles compositions. Altogether they suggest that DecP-11 antileishmanial activity is impaired by the aggregation and that aminophospholipids are probably involved. Conclusions: DecP-11 potent cytolytic and membranolytic activities with lack of selectivity toward promastigote model membranes warrant further structural studies to improve selectivity. (AU)

• Processo FAPESP: 13/50228-8 - Componentes da biodiversidade, e seus caracteres metabólicos, de ilhas do Brasil: uma abordagem integrada
• Beneficiário: Roberto Gomes de Souza Berlinck
• Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Temático
• Processo FAPESP: 14/11877-3 - Interações de peptideos bioativos e bicamadas lipídicas: valorizando a atividade leishmanicida
• Beneficiário: Maira Ramos Vieira
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 12/24259-0 - Moléculas conjugadas peptídeo/quitosana com potencial farmacológico: síntese, prospecção de atividade em sistemas miméticos de membrana e avaliações em células
• Beneficiário: Marcia Perez dos Santos Cabrera
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 14/08372-7 - Moléculas conjugadas peptídeo/quitosana com potencial farmacologico: síntese, prospecção de atividade em sistemas mimeticos de membrana e avaliações em células
• Beneficiário: Marcia Perez dos Santos Cabrera
• Modalidade de apoio: Bolsas no Brasil - Jovens Pesquisadores
• Processo FAPESP: 15/17331-5 - Efeitos de carga e hidrofobicidade nas interações de peptídeos com potencial ação leishmanicida e bicamadas lipídicas
• Beneficiário: Viviane Aparecida Camargo Santana
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica