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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.)

Synthesis, biophysical and functional studies of two BP100 analogues modified by a hydrophobic chain and a cyclic peptide

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Author(s):
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Carretero, Gustavo P. B. [1] ; Saraiva, V, Greice K. ; Cauz, Ana C. G. [2, 3] ; Rodrigues, Magali A. [4] ; Kiyota, Sumika [5] ; Riske, Karin A. [6] ; dos Santos, Alcindo A. [7] ; Pinatto-Botelho, Marcos F. [7] ; Bemquerer, Marcelo P. [4] ; Gueiros-Filho, Frederico J. [3] ; Chaimovich, Hernan [3] ; Schreier, Shirley [3] ; Cuccovia, Iolanda M. [3]
Total Authors: 13
Affiliation:
[1] Univ Sao Paulo, Inst Quim, Dept Bioquim, Sao Paulo - Brazil
[2] Univ Estadual Campinas, Inst Biol, Dept Genet Evolucao & Bioagentes, Campinas, SP - Brazil
[3] Saraiva, Greice K., V, Univ Sao Paulo, Inst Quim, Dept Bioquim, Sao Paulo - Brazil
[4] EMBRAPA Recursos Genet & Biotecnol, Parque Estacao Biol, Brasilia, DF - Brazil
[5] Inst Biol, Lab Bioquim Prot & Peptideos, Sao Paulo - Brazil
[6] Univ Fed Sao Paulo, Dept Biofis, Sao Paulo - Brazil
[7] Univ Sao Paulo, Inst Quim, Dept Quim Fundamental, Sao Paulo - Brazil
Total Affiliations: 7
Document type: Journal article
Source: BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES; v. 1860, n. 8, p. 1502-1516, AUG 2018.
Web of Science Citations: 6
Abstract

Antimicrobial peptides (AMPs) work as a primary defense against pathogenic microorganisms. BP100, (KKLF-KKILKYL-NH2), a rationally designed short, highly cationic AMP, acts against many bacteria, displaying low toxicity to eukaryotic cells. Previously we found that its mechanism of action depends on membrane surface charge and on peptide-to-lipid ratio. Here we present the synthesis of two BP100 analogs: BP100-alanyl-hexadecy1-1-amine (BP100-Ala-NH-C16H33) and cyclo(1-4)-D-Cys(1), Ile(2), Leu(3), Cys(4)-BP100 (Cyclo (1-4)-cILC-BP100). We examined their binding to large unilamellar vesicles (LUV), conformational and functional properties, and compared with those of BP100. The analogs bound to membranes with higher affinity and a lesser dependence on electrostatic forces than BP100. In the presence of LUV, BP100 and BP100-Ala-NH-C16H33 acquired a-helical conformation, while Cyclo(1-4)-cILC-BP100) was partly alpha-helical and partly beta-turn. Taking in conjunction: 1. particle sizes and zeta potential, 2. effects on lipid flip-flop, 3. leakage of LUVs internal contents, and 4. optical microscopy of giant unilamellar vesicles, we concluded that at high concentrations, all three peptides acted by a carpet mechanism, while at low concentrations the peptides acted by disorganizing the lipid bilayer, probably causing membrane thinning. The higher activity and lesser membrane surface charge dependence of the analogs was probably due to their greater hydrophobicity. The MIC values of both analogs towards Gram-positive and Gram-negative bacteria were similar to those of BP100 but both analogues were more hemolytic. Confocal microscopy showed Gram-positive B. subtilis killing with concomitant extensive membrane damage suggestive of lipid clustering, or peptide-lipid aggregation. These results were in agreement with those found in model membranes. (AU)

FAPESP's process: 13/08166-5 - Interfacial chemistry: drugs, peptides and ezymes interactions with membrane models
Grantee:Iolanda Midea Cuccovia
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 14/50983-3 - INCT 2014: complex fluids
Grantee:Antonio Martins Figueiredo Neto
Support Opportunities: Research Projects - Thematic Grants