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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
Martins, Danubia Batista [1] ; Vieira, Maira Ramos [2] ; Fadel, Valmir [1] ; Camargo Santana, Viviane Aparecida [2] ; Rodrigues Guerr, Mirian Elisa [1] ; Lima, Marta Lopes [3, 4] ; Tempone, Andre G. [4] ; dos Santos Cabrera, Marcia Perez [2, 1]
Total Authors: 8
Affiliation:
[1] Univ Estadual Paulista, Dept Fis, Sao Jose Do Rio Preto, SP - Brazil
[2] Univ Estadual Paulista, Dept Quim & Ciencias Ambientals, Sao Jose Do Rio Preto, SP - Brazil
[3] Univ Sao Paulo, Inst Med Trop, Sao Paulo, SP - Brazil
[4] Adolfo Lutz Inst, Ctr Parasitol & Mycol, Sao Paulo, SP - Brazil
Total Affiliations: 4
Document type: Journal article
Source: BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS; v. 1861, n. 11, A, p. 2861-2871, NOV 2017.
Web of Science Citations: 0
Abstract

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)

FAPESP's process: 13/50228-8 - Biodiversity components, and its metabolic characters, of Brazilian Islands
Grantee:Roberto Gomes de Souza Berlinck
Support type: BIOTA-FAPESP Program - Thematic Grants
FAPESP's process: 15/17331-5 - Charge and hydrophobicity effects on the interactions peptides with potential leishmanicidal activity and and lipid bilayers
Grantee:Viviane Aparecida Camargo Santana
Support type: Scholarships in Brazil - Scientific Initiation
FAPESP's process: 14/08372-7 - Peptide and chitosan conjugates with pharmacological potential: synthesis, prospecting of activity in membrane mimetic systems, and evaluation in cells
Grantee:Marcia Perez dos Santos Cabrera
Support type: Scholarships in Brazil - Young Researchers
FAPESP's process: 14/11877-3 - Interactions between bioactive peptides and lipid bilayers: prizing the leishmanicidal activity
Grantee:Maira Ramos Vieira
Support type: Scholarships in Brazil - Scientific Initiation
FAPESP's process: 12/24259-0 - Peptide and chitosan conjugates with pharmacological potential: synthesis, prospecting of activity in membrane mimetic systems, and evaluation in cells
Grantee:Marcia Perez dos Santos Cabrera
Support type: Research Grants - Young Investigators Grants