RESUMO
The synthesis, in vitro evaluation and conformational study of several small-size peptides acting as antibacterial agents are reported. Among the compounds evaluated, the peptides Arg-Gln-Ile-Lys-Ile-Trp-Arg-Arg-Met-Lys-Trp-Lys-Lys-NH2 , Arg-Gln-Ile-Lys-Ile-Arg-Arg-Met-Lys-Trp-Arg-NH2 , and Arg-Gln-Ile-Trp-Trp-Trp-Trp-Gln-Arg-NH2 exhibited significant antibacterial activity. These were found to be very active antibacterial compounds, considering their small molecular size. In order to better understand the antibacterial activity obtained for these peptides, an exhaustive conformational analysis was performed, using both theoretical calculations and experimental measurements. Molecular dynamics simulations using two different media (water and trifluoroethanol/water) were employed. The results of these theoretical calculations were corroborated by experimental circular dichroism measurements. A brief discussion on the possible mechanism of action of these peptides at molecular level is also presented. Some of the peptides reported here constitute very interesting structures to be used as starting compounds for the design of new small-size peptides possessing antibacterial activity.
Assuntos
Antibacterianos/química , Proteínas de Transporte/química , Oligopeptídeos/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Peptídeos Penetradores de Células , Escherichia coli/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Humanos , Testes de Sensibilidade Microbiana , Simulação de Dinâmica Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Conformação Proteica , Salmonella/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacosRESUMO
The synthesis, in vitro evaluation and conformational study of penetratin and structurally related derivatives acting as antibacterial agents are reported. Among the compounds evaluated here, two methionine sulphoxide derivatives (RQIKIWFQNRRM[O]KWKK-NH2 and RQIKIFFQNRRM[O]KFKK-NH2 ) exhibited the strongest antibacterial effect in this series. In order to better understand the antimicrobial activity obtained for these peptides, we performed an exhaustive conformational analysis using different approaches. Molecular dynamics simulations were performed using two different media (water and trifluoroethanol/water). The results of these theoretical calculations were corroborated using experimental CD measurements. The electronic study for these peptides was carried out using molecular electrostatic potentials obtained from RHF/6-31G(d) calculations. In addition, the non-apeptide RQIRRWWQR-NH2 showed strong inhibitory action against the Gram-negative and Gram-positive bacteria tested in this study.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Proteínas de Transporte/química , Proteínas de Transporte/farmacologia , Sequência de Aminoácidos , Infecções Bacterianas/tratamento farmacológico , Peptídeos Penetradores de Células , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Conformação ProteicaRESUMO
The synthesis, in vitro evaluation, and conformational study of penetratin analogues acting as antifungal agents are reported. Different peptides structurally related with penetratin were evaluated. Analogues of penetratin rich in Arg, Lys and Trp amino acids were tested. In addition, HFRWRQIKIWFQNRRM[O]KWKK-NH(2), a synthetic 20 amino acid peptide was also evaluated. These penetratin analogues displayed antifungal activity against human pathogenic strains including Candida albicans and Cryptococcus neoformans. In contrast, Tat peptide, a well-known cell penetrating peptide, did not show a significant antifungal activity against fungus tested here. We also performed a conformational study by means experimental and theoretical approaches (CD spectroscopic measurements and MD simulations). The electronic structure analysis was carried out from Molecular Electrostatic Potentials (MEP) obtained by using RHF/6-31G ab initio calculations. Our experimental and theoretical results permitted us to identify a topographical template which may provide a guide for the design of new peptides with antifungal effects.
Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Proteínas de Transporte/química , Proteínas de Transporte/farmacologia , Fungos/efeitos dos fármacos , Sequência de Aminoácidos , Peptídeos Penetradores de Células , Dicroísmo Circular , Simulação de Dinâmica Molecular , Dados de Sequência Molecular , Método de Monte Carlo , Conformação Proteica , Eletricidade EstáticaRESUMO
The synthesis, in vitro evaluation and conformational study of KKWKMRRNQFWIKIQR-NH(2), HFRWRQIKIWFQNRRMKWKK-NH(2) and RQPKIWFPNRRKPWKK-NH(2) acting as antifungal agents are reported. These peptides displayed a moderate but significant antifungal effect against both pathogenic fungi Candida albicans and Cryptococcus neoformans. The conformational analysis of these peptides was carried out using both theoretical and experimental methods.