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Phenylhydrazone-based Endoplasmic Reticulum Proteostasis Regulator Compounds with Enhanced Biological Activity
Biorxiv : the Preprint Server for Biology
|April 16, 2025
Summary
Researchers identified a new drug class that improves endoplasmic reticulum (ER) proteostasis by targeting protein disulfide isomerases. These compounds activate the ATF6 pathway, correcting protein misfolding in diseases like A1AT deficiency and epilepsy.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Endoplasmic reticulum (ER) proteostasis is crucial for preventing protein misfolding diseases.
- Existing compounds lack defined mechanisms for enhancing ER proteostasis.
- The compound AA263 was previously shown to promote ER proteostasis via ATF6 activation.
Purpose of the Study:
- To identify the protein target(s) of AA263.
- To develop improved analogs of AA263 for enhanced ER proteostasis regulation.
- To demonstrate the therapeutic potential of these analogs in protein misfolding disorders.
Main Methods:
- Chemical proteomics to identify AA263 targets.
- Medicinal chemistry to synthesize next-generation analogs.
- Cellular assays to assess ATF6 activation and proteostasis correction.
Main Results:
- AA263 covalently targets ER protein disulfide isomerases, explaining its ATF6 activation mechanism.
- Novel AA263 analogs exhibit enhanced potency and efficacy for ATF6 activation.
- These analogs correct protein misfolding and trafficking defects in α1-antitrypsin and GABAA receptor variants.
Conclusions:
- AA263 analogs represent a promising new class of ER proteostasis regulators.
- Targeting ER protein disulfide isomerases offers a viable strategy for treating protein misfolding diseases.
- These compounds show potential for correcting imbalanced ER proteostasis in diverse disorders.
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