Backbone-Determined Antiarrhythmic Structure-Activity Relationships for a Mirror Image, Oligomeric Depsipeptide...

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Natural Products

Background:

• Cyclic oligomeric depsipeptides (COD) are natural compounds with diverse biological activities.
• Verticilide inhibits insect ryanodine receptors (RyR).
• The enantiomer, ent-verticilide, potently inhibits mammalian RyR2, a cardiac calcium channel, suggesting antiarrhythmic potential.

Purpose of the Study:

• To develop ent-verticilide as a potential antiarrhythmic agent.
• To explore structure-activity relationships (SAR) of ent-verticilide analogs.
• To synthesize and test modified ent-verticilide compounds with altered ester functionality.

Main Methods:

• Systematic modification of ent-verticilide's ester functionality to N-H and N-Me amides.
• Synthesis of 23 ent-verticilide-inspired analogs using a monomer-based platform.
• Enantioselective catalysis for analog synthesis.
• Functional assay of RyR2 activity to measure calcium spark reduction.

Main Results:

• Two out of 23 synthesized analogs showed a measurable reduction in RyR2-mediated calcium sparks.
• This highlights the potential of the non-natural enantiomeric series for therapeutic development.
• Structure-activity relationship studies identified key modifications for RyR2 inhibition.

Conclusions:

• The study validates natural product-inspired drug development, particularly focusing on less-explored enantiomeric series.
• Ent-verticilide analogs represent a promising avenue for developing novel antiarrhythmic agents targeting RyR2.
• Further research into these non-natural enantiomers could yield significant therapeutic advancements.