Análogos de Histatina 5 complexados com íons metálicos de prata como alternativa para o combate a Candida albicans
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Data
2023-02-27
Autores
Zolin, Gabriela Vieira Silva
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Universidade Estadual Paulista (Unesp)
Resumo
A Candida albicans é principal causadora de infecções fúngicas. As limitadas classes de medicamentos disponíveis para o tratamento das infecções, assim como seu uso excessivo, potencializam o surgimento de resistência aos medicamentos. Peptídeos antimicrobianos (AMPs) foram identificados em diversos organismos e possuem diversas estruturas e funções, como atividades antimicrobianas e imunomoduladoras, e são candidatos promissores para o desenvolvimento de novos medicamentos antifúngicos. A histatina 5 é um AMP encontrado na cavidade oral, que possui a mais alta atividade antifúngica contra C. albicans, incluindo cepas resistentes aos agentes antifúngicos mais comumente usados. A atividade do peptídeo, porém, pode sofrer interferências na cavidade oral, bem proteólise mediada ou não pela C. albicans. Adaptações na estrutura do peptídeo, como o uso de fragmentos proteolíticos e a troca de resíduos de aminoácidos, foram empregados visando uma maior eficiência da ação antimicrobiana do peptídeo, bem como a redução da proteólise. O trabalho também propôs a coordenação dos peptídeos com íons metálicos de prata, como uma alternativa para o desenvolvimento de agentes antifúngicos. O uso de fragmentos bioativos contendo a porção C-terminal da Hst5 demonstraram atividade antifúngica otimizada em relação ao peptídeo original, e a troca de fragmentos de lisina por arginina foi capaz de aumentar a eficiência dos fragmentos proteolíticos. Os compostos de coordenação foram formados entre os peptídeos e Ag(I) na proporção molar 1:1, como comprovado pelos estudos de supressão de fluorescência e espectrometria de massas. Além disso, foi possível observar uma mudança na conformação dos peptídeos quando coordenados com Ag(I), perdendo a tendência de α-hélice, indicando uma associação na parte central das moléculas, pelas cadeias laterais dos resíduos de histidina. Os compostos de coordenação apresentaram forte ação antifúngica quando comparados aos peptídeos isolados, chegando a concentrações inibitórias mínimas de 10 e 20 μmol L-1 em diferentes cepas de C. albicans. Os peptídeos e compostos de coordenação foram avaliados quanto sua toxicidade, e apresentaram margem de segurança para uso como tratamentos antifúngicos em suas concentrações inibitórias mínimas.
Candida albicans is the main cause of fungal infections. The limited classes of drugs available for the infection’s treatment, as well as their excessive use, potentiate the emergence of drug resistance. Antimicrobial peptides (AMPs) have been identified in several organisms and have different structures and functions, such as antimicrobial and immunomodulatory activities, and are promising candidates for the development of new antifungal drugs. Histatin 5 is an AMP found in the oral cavity that has the highest antifungal activity against C. albicans, including strains resistant to the most used antifungal agents. The activity of the peptide, however, may suffer interference in the oral cavity, as well as proteolysis mediated or not by C. albicans. Adaptations in the peptide's structure, such as the use of proteolytic fragments and the exchange of amino acid residues, were employed aiming at a greater efficiency of the antimicrobial action of the peptide, as well as the reduction of proteolysis. The work also proposed the coordination of peptides with metallic silver ions, as an alternative for the development of antifungal agents. The use of bioactive fragments containing the C-terminal portion of Hst5 demonstrated optimized antifungal activity compared to the original peptide, and the exchange of lysine fragments for arginine was able to increase the efficiency of the proteolytic fragments. Coordination compounds were formed between peptides and Ag(I) in a 1:1 molar ratio, as confirmed by fluorescence suppression and mass spectrometry studies. Furthermore, it was possible to observe a change in the conformation of the peptides when coordinated with Ag(I), losing the α-helix tendency, indicating an association in the central part of the molecules, by the side chains of histidine residues. Coordination compounds showed strong antifungal action when compared to isolated peptides, reaching minimum inhibitory concentrations of 10 and 20 μmol L-1 in different strains of C. albicans. Peptides and coordination compounds were evaluated for their toxicity and showed a margin of safety for use as antifungal treatments at their minimum inhibitory concentrations.
Candida albicans is the main cause of fungal infections. The limited classes of drugs available for the infection’s treatment, as well as their excessive use, potentiate the emergence of drug resistance. Antimicrobial peptides (AMPs) have been identified in several organisms and have different structures and functions, such as antimicrobial and immunomodulatory activities, and are promising candidates for the development of new antifungal drugs. Histatin 5 is an AMP found in the oral cavity that has the highest antifungal activity against C. albicans, including strains resistant to the most used antifungal agents. The activity of the peptide, however, may suffer interference in the oral cavity, as well as proteolysis mediated or not by C. albicans. Adaptations in the peptide's structure, such as the use of proteolytic fragments and the exchange of amino acid residues, were employed aiming at a greater efficiency of the antimicrobial action of the peptide, as well as the reduction of proteolysis. The work also proposed the coordination of peptides with metallic silver ions, as an alternative for the development of antifungal agents. The use of bioactive fragments containing the C-terminal portion of Hst5 demonstrated optimized antifungal activity compared to the original peptide, and the exchange of lysine fragments for arginine was able to increase the efficiency of the proteolytic fragments. Coordination compounds were formed between peptides and Ag(I) in a 1:1 molar ratio, as confirmed by fluorescence suppression and mass spectrometry studies. Furthermore, it was possible to observe a change in the conformation of the peptides when coordinated with Ag(I), losing the α-helix tendency, indicating an association in the central part of the molecules, by the side chains of histidine residues. Coordination compounds showed strong antifungal action when compared to isolated peptides, reaching minimum inhibitory concentrations of 10 and 20 μmol L-1 in different strains of C. albicans. Peptides and coordination compounds were evaluated for their toxicity and showed a margin of safety for use as antifungal treatments at their minimum inhibitory concentrations.
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Palavras-chave
Peptídeos catiônicos antimicrobianos, Candida albicans, Compostos de coordenação, Antifungal agents