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Diene Substitution Patterns in the Conformation-Activity Relationships of GEX1A
Christian A Umaña1, Matthew C Rhodes1, Jeffrey L Henry1
1Department of Chemistry and Biochemistry and the Warren Center for Drug Discovery, University of Notre Dame, Notre Dame, Indiana, USA.
Chemmedchem
|May 22, 2026
Summary
GEX1A, a natural product, impacts pre-mRNA splicing and cholesterol levels. Modifying its diene section significantly alters GEX1A
Area of Science:
- Natural Products Chemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- GEX1A (herboxidiene) is a polyketide with significant biological activities.
- GEX1A inhibits pre-mRNA splicing by binding SF3B1 and reverses cholesterol accumulation in Niemann-Pick Type C fibroblasts.
- Previous structure-activity relationship studies focused on the tetrahydropyran core and side chain.
Purpose of the Study:
- To explore the impact of substitutions on the diene section of GEX1A.
- To synthesize and characterize novel GEX1A analogues.
- To establish a conformational-activity profile for GEX1A analogues.
Main Methods:
- Design and synthesis of GEX1A analogues with modifications on the diene section.
- Computational studies to analyze conformational landscapes.
- High-field Nuclear Magnetic Resonance (NMR) spectroscopy to determine conformation.
- Assessment of biological activities of synthesized analogues.
Main Results:
- Successful synthesis of GEX1A analogues with diene section modifications.
- Computational and NMR studies revealed distinct conformational landscapes for the analogues.
- Modifications on the diene section significantly altered the biological activities of GEX1A.
- Established a correlation between conformation and biological activity for the diene-modified analogues.
Conclusions:
- The diene section of GEX1A is a critical determinant of its conformational preferences and biological functions.
- Targeted modifications of the diene moiety offer a strategy for developing novel GEX1A-based therapeutics.
- Understanding the conformational-activity relationship is key for optimizing GEX1A's therapeutic potential.
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