Oximic compounds as potential inhibitors of metacaspase-2 (TbMCA2) of Trypanosoma brucei

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Araujo, Laura Helena ; Chagas, Thaynan Aparecida Bueno ; Reis, Taiz ; Borba, Joao Ricardo Bueno de Morais ; Trujilho, Mariana Nascimento Romero ; Dalzoto, Laura de Azevedo Maffeis ; Marcondes, Marcelo Ferreira ; Juliano, Maria Aparecida ; Judice, Wagner Alves de Souza ; Veloso, Marcia Paranho ; Machado, Mauricio Ferreira Marcondes

• Tipo de documento: Artigo Científico
• Fonte: Biochemical and Biophysical Research Communications; v. 735, p. 12-pg., 2024-09-11.

Resumo

Metacaspases are a distinct class of cysteine proteases predominantly found in plants, fungi, and protozoa, crucial for regulating programmed cell death (PCD). They possess unique structural features and differ markedly from caspases in their activation mechanisms and substrate specificities, with a notable preference for binding basic residues in substrates. In this study, we introduced vanillin-derived oximic compounds to explore their pharmaceutical potential. We evaluated these compounds for their inhibitory effects on TbMCA2, a metacaspase in Trypanosoma brucei, identifying AO-7, AO-12, and EO-20 as promising inhibitors. AO-12 showed significant potential as a non-competitive inhibitor with notable IC50 values. Molecular docking studies were also conducted to evaluate the binding affinity of these compounds for TbMCA2. This research is particularly relevant given the urgent need for more effective and less toxic treatments for trypanosomiasis, a parasitic disease caused by trypanosomes. The absence of available vaccines and the limitations imposed by drug toxicity underscore the importance of these findings. Our study represents a significant advancement in developing therapeutic agents targeting metacaspases in trypanosomatids and highlights the necessity of understanding metacaspase regulation across various species. It provides valuable insights into inhibitor sensitivity and potential species-specific therapeutic strategies. In conclusion, this research opens promising avenues for novel therapeutic agents targeting metacaspases in trypanosomatids, addressing a critical gap in combating neglected diseases associated with these pathogens. Further research is essential to refine the efficacy and safety profiles of these compounds, aiming to deliver more accessible and effective therapeutic solutions to populations afflicted by these debilitating diseases. (AU)

• Processo FAPESP: 22/06394-0 - Obtenção e caracterização bioquímica de metacaspases recombinantes de protozoários de interesse clínico
• Beneficiário: Mauricio Ferreira Marcondes Machado
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 19/27813-8 - Desenvolvimento de inibidores de beta-lactamases de interesse clínico
• Beneficiário: Marcelo Ferreira Marcondes Machado
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 21/01503-2 - Avaliação dos efeitos de glicosaminoglicanos na atividade de inibidores de cisteíno proteases catepsinas
• Beneficiário: Wagner Alves de Souza Júdice
• Modalidade de apoio: Auxílio à Pesquisa - Regular