What is it about?
Muscle and heart cells rely on tiny “gates” called ryanodine receptors to release calcium and trigger each heart beat or muscle contraction. In our work, we screened safe, caffeine‐related chemicals to see if any could gently nudge these gates open more easily. Using detailed 3D images and mouse tests, we found several xanthine compounds and the common gout drug allopurinol that bind to the receptor and make it function more. These compounds don’t become medicines as they are, but they serve as promising “drug‑like” starting points. By refining these hits, researchers could develop new therapies to strengthen weak hearts or aging muscles without having to invent entirely new drug families.
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Why is it important?
This work matters because weak calcium signals underlie a wide range of muscle problems—from the tens of millions of adults with heart failure or age‑related muscle weakness to children born with rare genetic myopathies that currently have no cure. By revealing exactly how simple xanthine molecules (the same core structure found in allopurinol) bind to and “prime” the ryanodine receptor, we’ve identified ready‑made chemical scaffolds that boost calcium release in muscle cells. Medicinal chemists can now take these drug‑like hits and rapidly optimize them, cutting years off the typical discovery process and lowering development costs. Ultimately, this approach could lead to first‑in‑class therapies that strengthen weak hearts and muscles in patients of all ages.
Perspectives
The neglect of targeted therapies for heart and muscle weakness has left a vast unmet need. Despite the immense burden of these conditions, few biotech or pharmaceutical programs focus on directly enhancing contraction or calcium release mechanisms. I believe that by highlighting xanthine-based scaffolds as concrete starting points, our work could spark a paradigm shift in drug discovery. This approach not only diversifies the mechanistic strategies beyond conventional pathways but also opens doors for collaboration between structural biologists, chemists, and clinicians. Ultimately, I envision this research catalyzing a new wave of therapeutics that bring hope to patients with both common and rare muscle disorders.
MARCO MIOTTO
Columbia University
Read the Original
This page is a summary of: Targeting ryanodine receptors with allopurinol and xanthine derivatives for the treatment of cardiac and musculoskeletal weakness disorders, Proceedings of the National Academy of Sciences, June 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2422082122.
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