Estudo de inibição da leader protease Lbpro via ligação do grupo Tiol usando teluretos orgânicos

• Ano de defesa: 2019
• Autor(a) principal: Santos Junior, Gilberto Alves Dos [UNIFESP]
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Cysteine Proteinase Inhibitors; Foot-And-Mouth Disease; Tellurium; Papain
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=7838687; https://repositorio.unifesp.br/handle/11600/59648

The Foot-and-mouth disease (FMD) is a highly contagious viral disease that infects animals such as cattle, goats, sheep, pigs and rarely affect humans. The high prevalence of disease directly affects the economy of countries including Brazil, as the international trade of animal foods is controlled by strictly phytosanitary regulations. Foot-and-mouth disease currently has no treatment, and vaccines consists the mainly prophylaxis. Its etiologic agent is an RNA virus of the Picornaviridae family, which is translated into a single polyprotein that, after processing, releases structural and non-structural proteins by specific viral proteases. Among these proteases, and object of this study, the Leader Proteases (Lbpro.) is a potential target for the development of chemotherapeutic agents. Lbpro is a cysteine-peptidase and the covalent attachment of tellurium compounds to the thiol group of cysteine residues in its catalytic site is therefore a target for blocking its activity, directly interfering the virus processing, maturation and replication. The objective of the present work was to develop and characterize inhibitors possessing the Tellurium atom as the core agent against the proteolytic activity of Lbpro. To do so, we performed kinetic assays to inhibit the activity of this enzyme using a library of structurally different organic tellurium-derived compounds capable of inhibiting cysteine-peptidases by forming covalent bond between the multivalence Tellurium atom and the catalytic free thiol group of Lbpro. The specificity of Lbpro by the inhibitors was measured by the comparative assay using the papain cysteine-peptidase as reference. Our results indicate that larger organic compounds having central tellurium atom were better inhibitors of Lbpro because provide more interactions between the Lbpro activity residues and inhibitors due to symmetrical docking, contrasting to Papain selectivity. Thus, such active-site inhibitors of cysteine-proteases are promising to evaluate the singular specificities and features of Lbpro and proteases-targeted drug design.