Targeting ryanodine receptors with allopurinol and xanthine derivatives for the treatment of cardiac and musculoskeletal weakness disorders

TL;DR

This paper explores using allopurinol and xanthine derivatives to improve muscle function by targeting ryanodine receptors, potentially treating heart and muscle weakness.

Contribution

The study identifies 4-oxopyrimidine as the minimal chemical motif for activating ryanodine receptors using xanthine derivatives.

Findings

Xanthine derivatives bind to and activate ryanodine receptors via a specific binding site.

4-oxopyrimidine is the minimal motif required for ryanodine receptor activation.

Allopurinol and xanthine derivatives show potential for treating muscle and heart diseases.

Abstract

Cardiac and skeletal muscle weakness are serious health problems resulting from hereditary or age-related diseases. We study the ryanodine receptors, proteins that play an essential role in cardiac and skeletal muscle contraction. Genetic variations in ryanodine receptors lead to debilitating and deadly diseases. Age-related changes in the expression or function of ryanodine receptors play a role in the development of heart failure and sarcopenia. Our aim is to develop drugs that bind to and improve the function of ryanodine receptors, resulting in improved cardiac and skeletal muscle contraction. Using cryo-EM, we determined the minimal chemical motif for compounds to bind to and activate ryanodine receptors, opening avenues to develop drugs for potential therapeutic use.

Ryanodine receptors (RyRs) are intracellular Ca2+ channels essential for muscle contraction. Caffeine, a xanthine derivative, has been known for decades to increase muscle contraction and enhance activation of RyRs by increasing the sensitivity to Ca2+. We previously showed that xanthine, the only physiologically relevant xanthine derivative, also binds to and activates RyR2. Most xanthine derivatives and analogs are safe and widely prescribed, with the most popular being the xanthine oxidoreductase inhibitor allopurinol (~15M yearly prescriptions in USA). We propose that xanthine derivatives and analogs that enhance RyRs activity could be used for lead optimization and eventually for the treatment of the diseases that exhibit decreased muscle contraction and reduced RyRs activity, such as RyR1-related diseases, sarcopenia, and heart failure. Here, we show by cryo-EM that xanthine derivatives, analogs, and other related compounds bind to the xanthine/caffeine binding site and activate RyR1, and identify 4-oxopyrimidine as the minimal motif necessary for such interaction.

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