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

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: United States NLM ID: 0372516 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2104 (Electronic) Linking ISSN: 0006291X NLM ISO Abbreviation: Biochem Biophys Res Commun Subsets: MEDLINE
    • Publication Information:
      Publication: <2002- >: San Diego, CA : Elsevier
      Original Publication: New York, Academic Press.
    • Subject Terms:
      Trypanosoma brucei brucei*/enzymology ; Trypanosoma brucei brucei*/drug effects ; Molecular Docking Simulation* ; Caspases*/metabolism ; Caspases*/chemistry; Caspase Inhibitors/pharmacology ; Caspase Inhibitors/chemistry ; Benzaldehydes/pharmacology ; Benzaldehydes/chemistry ; Protozoan Proteins/antagonists & inhibitors ; Protozoan Proteins/metabolism ; Protozoan Proteins/chemistry ; Trypanocidal Agents/pharmacology ; Trypanocidal Agents/chemistry
    • Abstract:
      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 IC 50 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.
      Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2024 Elsevier Inc. All rights reserved.)
    • Contributed Indexing:
      Keywords: Inhibition; Inhibition mechanism; Metacaspase; Oximic compounds
    • Accession Number:
      EC 3.4.22.- (Caspases)
      0 (Caspase Inhibitors)
      0 (Benzaldehydes)
      0 (Protozoan Proteins)
      0 (Trypanocidal Agents)
      CHI530446X (vanillin)
    • Publication Date:
      Date Created: 20240912 Date Completed: 20241104 Latest Revision: 20241107
    • Publication Date:
      20241108
    • Accession Number:
      10.1016/j.bbrc.2024.150657
    • Accession Number:
      39265363