Synthesis and properties of cyclic gomesin and analogues

Abstract

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 [Thr(2,6,11,15),(D)-Pro(9)]-Gm (no disulfide bonds) were accomplished, and the impact of cyclization on their properties was examined. The consequence of simultaneous deletion of pGlu(1) and Arg(16) -Glu-Arg(18) -NH(2) 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 °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 pGlu(1) and the amidated C-terminal tripeptide Arg(16) -Glu-Arg(18) -NH(2) 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 [Thr(2,6,11,15),(D)-Pro(9)]-Gm analogue remains the best active Gm-derived AMP developed so far; nevertheless, its elevated instability in human serum may limit its therapeutic potential.

Small lipidated anti-obesity compounds derived from neuromedin U

“…Alternatively, loss of their activity may involve partial hydrolysis of the N-terminal N 7 -amide to α- or β-monocarboxylic acid residues (X-Asn-OH or X-Asp-NH 2 ) via an aminosuccinimide intermediate [22]. Therefore we performed plasma stability studies for both NM4A and NM4-C 16 analogs using full length hNmU as a comparator [67–69]. Results (Figure 5C) indicated that both analogs have significant resistance to mouse plasma driven enzymatic degradation, with NM4-C 16 being more stable than NM4A.…”

Hemocidinas derivadas da hemoglobina: estruturas, propriedades e perspectivas

“…Relatos na literatura indicam maior resistência à proteólise do AMP com a amidação da sua porção C-terminal 34 ou ciclização envolvendo aminoácidos D e L. 53 Em relação ao alto custo de produção, estudos da relação estrutura-atividade vem sendo realizados com o objetivo de gerar peptídeos menores, portanto, mais baratos, tão ou mais ativos do que os naturais. 53 Quanto à redução de potência em alta força iônica, pesquisas indicam que mudanças na hidrofobicidade, anfipaticidade, carga e grau de a-hélice auxiliam a solucionar o problema. 53 Assim, pode-se comparar os AMPs e os antimicrobianos disponíveis no mercado (Tabela 2).…”

“…53 Quanto à redução de potência em alta força iônica, pesquisas indicam que mudanças na hidrofobicidade, anfipaticidade, carga e grau de a-hélice auxiliam a solucionar o problema. 53 Assim, pode-se comparar os AMPs e os antimicrobianos disponíveis no mercado (Tabela 2).…”

The role of imidazole in peptide cyclization by transesterification: parallels to the catalytic triads of serine proteases

“…Examples of such structures are cyclic depsipeptides, 2 glutathione, the conotoxins, 3 and the trypsin inhibitor SFTI-1, with a single disulfide bridge. 4 The biological and medical significance of cyclic peptides as potential therapeutics is evinced by an increasing number of publications describing their antiviral, 5 hemolytic 6 and anti-helminthic 7 activities. Cyclic peptides owe at least a part of their importance in nature to their tendency to resist degradation by exopeptidases.…”