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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Synthesis and properties of cyclic gomesin and analogues

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Autor(es):
Machado, Alessandra [1, 2] ; Fazio, Marcos A. [3, 4] ; Miranda, Antonio [3] ; Daffre, Sirlei [5] ; Teresa Machini, M. [1]
Número total de Autores: 5
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Inst Chem, Dept Biochem, BR-05513970 Sao Paulo - Brazil
[2] Univ Tecnol Fed Parana, Francisco Beltrao, PR - Brazil
[3] Univ Fed Sao Paulo, Dept Biophys, Sao Paulo - Brazil
[4] Univ Prebiteriana Mackenzie, Sao Paulo - Brazil
[5] Univ Sao Paulo, Inst Biomed Sci, Dept Biochem, BR-05513970 Sao Paulo - Brazil
Número total de Afiliações: 5
Tipo de documento: Artigo Científico
Fonte: JOURNAL OF PEPTIDE SCIENCE; v. 18, n. 9, p. 588-598, SEP 2012.
Citações Web of Science: 9
Resumo

Gomesin (Gm) was the first antimicrobial peptide (AMP) isolated from the hemocytes of a spider, the Brazilian mygalomorph Acanthoscurria gomesiana. We have been studying the properties of this interesting AMP, which also displays anticancer, antimalarial, anticryptococcal and anti-Leishmania activities. In the present study, the total syntheses of backbone-cyclized analogues of Gm (two disulfide bonds), {[}Cys(Acm)2,15]-Gm (one disulfide bond) and {[}Thr2,6,11,15,d-Pro9]-Gm (no disulfide bonds) were accomplished, and the impact of cyclization on their properties was examined. The consequence of simultaneous deletion of pGlu1 and Arg16-Glu-Arg18-NH2 on Gm antimicrobial activity and structure was also analyzed. The results obtained showed that the synthetic route that includes peptide backbone cyclization on resin was advantageous and that a combination of 20% DMSO/NMP, EDC/HOBt, 60?degrees C and conventional heating appears to be particularly suitable for backbone cyclization of bioactive peptides. The biological properties of the Gm analogues clearly revealed that the N-terminal amino acid pGlu1 and the amidated C-terminal tripeptide Arg16-Glu-Arg18-NH2 play a major role in the interaction of Gm with the target membranes. Moreover, backbone cyclization practically did not affect the stability of the peptides in human serum; it also did not affect or enhanced hemolytic activity, but induced selectivity and, in some cases, discrete enhancements of antimicrobial activity and salt tolerance. Because of its high therapeutic index, easy synthesis and lower cost, the {[}Thr2,6,11,15,d-Pro9]-Gm analogue remains the best active Gm-derived AMP developed so far; nevertheless, its elevated instability in human serum may limit its therapeutic potential. Copyright (c) 2012 European Peptide Society and John Wiley \& Sons, Ltd. (AU)

Processo FAPESP: 01/02270-8 - Análogo cíclico "cabeça-cauda" da gomesina: busca de alternativas metodológicas para a sua obtenção e avaliação do efeito de ciclização nas atividades antimicrobiana e hemolítica
Beneficiário:Alessandra Machado Lunkes
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 01/11296-0 - Síntese de peptídeos de conformação restrita via ciclização cabeça-cauda e formação de ligação lactama
Beneficiário:Maria Teresa Machini
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 00/05410-2 - Diferentes aspectos da síntese de peptpídeos longos e de sequências difíceis: parte II
Beneficiário:Maria Teresa Machini
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 08/11695-1 - Tecnologias alternativas na química de peptídeos: solvólise mediada por íons metálicos, biocatálise, aquecimento convencional e microondas
Beneficiário:Maria Teresa Machini
Linha de fomento: Auxílio à Pesquisa - Regular