Design, Synthesis, and Biological Evaluation of Eukaryotic Initiation Factor 2B (eIF2B) Activators

Area of Science:

• Biochemistry
• Neuroscience
• Medicinal Chemistry

Background:

• Eukaryotic initiation factor 2B (eIF2B) is crucial for protein synthesis and central nervous system function.
• Dysregulation of eIF2B is implicated in neurodegenerative diseases like Alzheimer's, ALS, and VWM.
• Targeting eIF2B offers a therapeutic strategy for these debilitating conditions.

Purpose of the Study:

• To design and synthesize novel oxadiazole-containing compounds as eIF2B activators.
• To evaluate the efficacy of these compounds in modulating eIF2B activity and their potential therapeutic applications.

Main Methods:

• Synthesis of novel oxadiazole derivatives.
• Assay of ATF4 expression inhibition to assess eIF2B activation.
• ATF4 mRNA and protein translation assays in stimulated cells.
• Cytotoxicity assays to determine compound safety.

Main Results:

• Compounds 21 and 29 demonstrated potent inhibition of ATF4 expression (IC50 values of 32.43 nM and 47.71 nM, respectively), outperforming ISRIB.
• These compounds effectively restored ATF4 mRNA levels and protein synthesis in thapsigargin-stimulated HeLa cells.
• Compounds 21 and 29 exhibited low toxicity and comparable potency to ISRIB in protein translation assays.

Conclusions:

• Novel oxadiazole compounds, particularly 21 and 29, are effective eIF2B activators.
• These compounds show promise as therapeutic agents for neurodegenerative diseases.
• Further investigation into compounds 21 and 29 is warranted due to their potency and low toxicity.