Estudos da atividade biológica de peptídeos do veneno de artrópodes
Data
2024-04-05
Autores
Oliveira, Cyntia Silva de 
Orientadores
Oliveira Junior, Vani Xavier de
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Peptídeos de Defesa do Hospedeiro (PDHs) é uma denominação mais abrangente para o termo peptídeos antimicrobianos, uma vez que essas complexas moléculas, componentes do sistema imune inato, apresentam uma grande variedade de atividades biológicas; além da clássica atividade antimicrobiana, eles podem atuar como antitumorais, antibiofilmes, imunomoduladores e anti-inflamatórios, entre outros. Este estudo investigou as propriedades biológicas de versões sintéticas de PDHs, provenientes do veneno da vespa Polistes dominulus e do escorpião Opisthacanthus madagascariensis, bem como seus análogos sintéticos, incluindo análises estruturais, atividade antimicrobiana, citotóxica e antitumoral. Os PDHs de vespa, Dominulin A (DomA) e Dominulin B (DomB), são peptídeos catiônicos α-helicoidais, que apresentam elevada atividade antimicrobiana contra uma variedade de bactérias em concentrações micromolares. Ambos, apresentaram, também, promissora atividade contra células de câncer de mama, com atividade mais proeminente contra o fenótipo mais agressivo. O design de análogos truncados, denominados 14-DomA e 14-DomB, mostrou-se uma ferramenta útil para a obtenção de seletividade biológica, gerando moléculas com atividade antimicrobiana, sem proporcionar citotoxicidade contra células humanas. Por sua vez, o peptídeo de escorpião IsCT1 e seus análogos, com diferentes cargas líquidas, revelaram uma complexa relação entre estrutura e atividade antitumoral e citotóxica, mostrando que o aumento da carga líquida não possui correlação direta com a atividade antitumoral; por outro lado, foi observada a importância da estruturação helicoidal na manutenção da atividade biológica desse grupo de peptídeos. Dentre os análogos do IsCT1, o AKFK-IsCT1, desenhado com aumento moderado da carga líquida e estruturação helicoidal semelhante ao seu peptídeo nativo, apresentou proeminente redução da atividade citotóxica e hemolítica, mantendo relevante atividade antitumoral. Esse análogo mostrou grande atividade sinérgica com a terapia fotodinâmica, além de apresentar potencial imunomodulatório, em modelo animal, para câncer de mama. Esses achados fornecem insights valiosos sobre a estrutura e atividade biológica dos PDHs e de seus análogos sintéticos, destacando seu potencial como agentes promissores em diversas aplicações terapêuticas. A compreensão das propriedades e modos de ação dos PDHs pode contribuir significativamente para o desenvolvimento de novas estratégias terapêuticas, especialmente na luta contra doenças infecciosas e câncer, alinhando-se com os objetivos de saúde global preconizados pela Organização Mundial da Saúde.
Host Defense Peptides (PDHs) is a more comprehensive term for previously antimicrobial peptides named, because these complex molecules of the innate immune system present a wide range of biological activities, in addition to the classic antimicrobial activity, and can act as antitumor, antibiofilm, immunomodulatory, anti-inflammatory, among others. This study investigated the biological properties of synthetic versions of PDHs from the venom of the wasp Polistes dominulus and the scorpion Opisthacanthus madagascariensis, as well as their synthetic analogs, including structural analysis, antimicrobial, cytotoxic, and antitumor activity. The wasp PDHs, Dominulin A (DomA) and Dominulin B (DomB) are α-helical cationic peptides, that exhibit high antimicrobial activity against different types of bacteria at micromolar concentrations. Both PDHs showed promising activity against breast cancer cells, with more prominent activity against the more aggressive phenotype. The design of truncated analogs, 14-DomA and 14-DomB, proved useful for obtaining biological selectivity, generating molecules with antimicrobial activity, without cytotoxicity against human cells. In turn, the scorpion peptide IsCT1, and its analogs designed with different net charges, revealed a complex relationship between structure and antitumor and cytotoxic activity, showing that the increase in net charge does not have a direct correlation with antitumor activity, highlighting the importance of helical structuring in maintaining biological activity in this group of peptides. Among the IsCT1 analogs, AKFK-IsCT1, designed with a moderate increase in net charge and helical structuring similar to its native peptide, showed a prominent reduction in cytotoxic and hemolytic activity, while maintaining relevant antitumor activity. This same analog showed great synergistic activity with photodynamic therapy and immunomodulatory potential in an animal model for breast cancer. These findings provide valuable insights into the structure and biological activity of PDHs and their synthetic analogs, highlighting their potential as promising agents in diverse therapeutic applications. Understanding the properties and modes of action of PDHs contributes significantly to the new therapeutic strategies development, especially in line with the global health objectives recommended by the World Health Organization, in the fight against cancer and infectious diseases.
Host Defense Peptides (PDHs) is a more comprehensive term for previously antimicrobial peptides named, because these complex molecules of the innate immune system present a wide range of biological activities, in addition to the classic antimicrobial activity, and can act as antitumor, antibiofilm, immunomodulatory, anti-inflammatory, among others. This study investigated the biological properties of synthetic versions of PDHs from the venom of the wasp Polistes dominulus and the scorpion Opisthacanthus madagascariensis, as well as their synthetic analogs, including structural analysis, antimicrobial, cytotoxic, and antitumor activity. The wasp PDHs, Dominulin A (DomA) and Dominulin B (DomB) are α-helical cationic peptides, that exhibit high antimicrobial activity against different types of bacteria at micromolar concentrations. Both PDHs showed promising activity against breast cancer cells, with more prominent activity against the more aggressive phenotype. The design of truncated analogs, 14-DomA and 14-DomB, proved useful for obtaining biological selectivity, generating molecules with antimicrobial activity, without cytotoxicity against human cells. In turn, the scorpion peptide IsCT1, and its analogs designed with different net charges, revealed a complex relationship between structure and antitumor and cytotoxic activity, showing that the increase in net charge does not have a direct correlation with antitumor activity, highlighting the importance of helical structuring in maintaining biological activity in this group of peptides. Among the IsCT1 analogs, AKFK-IsCT1, designed with a moderate increase in net charge and helical structuring similar to its native peptide, showed a prominent reduction in cytotoxic and hemolytic activity, while maintaining relevant antitumor activity. This same analog showed great synergistic activity with photodynamic therapy and immunomodulatory potential in an animal model for breast cancer. These findings provide valuable insights into the structure and biological activity of PDHs and their synthetic analogs, highlighting their potential as promising agents in diverse therapeutic applications. Understanding the properties and modes of action of PDHs contributes significantly to the new therapeutic strategies development, especially in line with the global health objectives recommended by the World Health Organization, in the fight against cancer and infectious diseases.
Descrição
Citação
OLIVEIRA, Cyntia Silva de. Estudos da atividade biológica de peptídeos do veneno de artrópodes. 2024. 126 f. Tese (Doutorado em Biologia Molecular) - Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, 2024.