Phenylhydrazone-based endoplasmic reticulum proteostasis regulator compounds with enhanced biological activity

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Pharmacological enhancement of endoplasmic reticulum (ER) proteostasis is a promising strategy for protein misfolding diseases.
• Few compounds effectively enhance ER proteostasis via defined mechanisms.
• Previous work identified AA263 as a promoter of ER proteostasis, activating the ATF6 pathway.

Purpose of the Study:

• To identify the molecular targets of AA263.
• To develop improved analogs of AA263 for enhanced ER proteostasis regulation.
• To assess the therapeutic potential of these analogs in protein misfolding disease models.

Main Methods:

• Chemical proteomics was used to identify AA263 targets.
• Medicinal chemistry was employed to synthesize next-generation AA263 analogs.
• The analogs' efficacy was tested in cellular models of α1-antitrypsin (A1AT) and GABA_A receptor variants.

Main Results:

• AA263 was found to covalently target ER protein disulfide isomerases, elucidating its mechanism for ATF6 activation.
• New AA263 analogs demonstrated improved potency and efficacy in activating ATF6.
• Treatment with AA263 analogs corrected protein misfolding and trafficking defects in A1AT and GABA_A receptor variants.

Conclusions:

• AA263 analogs represent a novel class of ER proteostasis regulators.
• These compounds offer enhanced potential for treating diverse protein misfolding disorders.
• Targeting ER protein disulfide isomerases provides a viable strategy for therapeutic intervention.