Predição e desenho racional assistido por computador para bioprospecção de novos peptídeos antimicrobianos

• Ano de defesa: 2017
• Autor(a) principal: Porto, William Farias
• Orientador(a): Franco, Octávio Luiz
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Católica de Brasília
• Programa de Pós-Graduação: Programa Stricto Sensu em Ciências Genômicas e Biotecnologia
• Departamento: Escola de Saúde e Medicina
• País: Brasil
• Palavras-chave em Português: Algoritmo genético; Análises estruturais; Infecções bacterianas; Peptídeos antimicrobianos - PAMs; SNPs
• Palavras-chave em Inglês: Bacterial infections; Structural analysis; Genetic algorithm
• Área do conhecimento CNPq: CNPQ::CIENCIAS BIOLOGICAS::GENETICA
• Resumo em Inglês: Antimicrobial peptides (AMPs) are part of the innate immune system. Genetic modifications can lead to the imbalance in the production of AMPs, which in turn, can lead to several inflammatory and/or infectious conditions. In this context, the identification and characterization of AMPs variants caused by point mutations are important to medical monitoring of bearers of such mutations; mainly due to the fact that the effectiveness of conventional antimicrobial agents has been reduced due to the development of resistance by bacteria, a breakthrough of new drugs is made. In this context, synthetic AMPs, generated through several rational design methods, have been proposed as an alternative. Thus, aiming at solutions to this scenario, the present work presents two new approaches, which consist of a model for the prediction of activities of variants of human defensins; and the computer-aided design of plant peptides. In the first approach, it was elaborated a system of median lethal dose prediction, correlating previously published data and the solvation potential energy of the variants. This model was applied to human defenses, HD5 and HBD1, which in turn showed that several variants may be less potent and consequently their carriers may be more susceptible to bacterial infections. In this way, in the second approach, the guava peptide, Pg-AMP1, was used as a model for the development of new synthetic peptides, the guavanins. Structural analyzes of Pg- AMP1 indicated an extremely flexible and variable structure. Thus, a genetic algorithm for computer-aided rational design was applied to obtain a more stable structure. The prototype, guavanin 2, presented α-helix structuring in hydrophobic environments, and showed 100% efficacy against Gram-negative bacteria at low concentrations through the rupture of the bacterial membrane and causing hyperpolarization of the same. In sum, the methodologies and the molecules developed here bring new perspectives for the treatment of infections.
• Link de acesso: https://bdtd.ucb.br:8443/jspui/handle/tede/2458

Antimicrobial peptides (AMPs) are part of the innate immune system. Genetic modifications can lead to the imbalance in the production of AMPs, which in turn, can lead to several inflammatory and/or infectious conditions. In this context, the identification and characterization of AMPs variants caused by point mutations are important to medical monitoring of bearers of such mutations; mainly due to the fact that the effectiveness of conventional antimicrobial agents has been reduced due to the development of resistance by bacteria, a breakthrough of new drugs is made. In this context, synthetic AMPs, generated through several rational design methods, have been proposed as an alternative. Thus, aiming at solutions to this scenario, the present work presents two new approaches, which consist of a model for the prediction of activities of variants of human defensins; and the computer-aided design of plant peptides. In the first approach, it was elaborated a system of median lethal dose prediction, correlating previously published data and the solvation potential energy of the variants. This model was applied to human defenses, HD5 and HBD1, which in turn showed that several variants may be less potent and consequently their carriers may be more susceptible to bacterial infections. In this way, in the second approach, the guava peptide, Pg-AMP1, was used as a model for the development of new synthetic peptides, the guavanins. Structural analyzes of Pg- AMP1 indicated an extremely flexible and variable structure. Thus, a genetic algorithm for computer-aided rational design was applied to obtain a more stable structure. The prototype, guavanin 2, presented α-helix structuring in hydrophobic environments, and showed 100% efficacy against Gram-negative bacteria at low concentrations through the rupture of the bacterial membrane and causing hyperpolarization of the same. In sum, the methodologies and the molecules developed here bring new perspectives for the treatment of infections.