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Related Experiment Videos

Designer small molecules to target calcium signalling.

Joanna M Swarbrick1, Andrew M Riley1, Stephen J Mills1

  • 1*Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, U.K.

Biochemical Society Transactions
|May 27, 2015
PubMed
Summary

Synthetic compounds are revolutionizing the study of calcium (Ca2+) signaling pathways. New chemical tools offer insights into diseases and potential drug development for conditions like heart arrhythmia and autoimmune disorders.

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Area of Science:

  • Chemical Biology
  • Molecular Pharmacology
  • Medicinal Chemistry

Background:

  • Intracellular calcium (Ca2+) signaling pathways are crucial for numerous cellular processes.
  • Dysregulation of Ca2+ signaling is implicated in various diseases.
  • Development of precise chemical tools is essential for understanding and manipulating these pathways.

Purpose of the Study:

  • To describe recent advances in synthetic chemical biology tools for probing Ca2+ signaling.
  • To highlight synthetic analogues that enhance biological understanding or offer potential as drug-like molecules.
  • To explore novel chemical entities for targeting specific Ca2+ channels and receptors.

Main Methods:

  • Total synthesis of modified signaling molecules, including adenophostin (AdA) analogues, inositol 1,4,5-trisphosphate (IP3) derivatives, biphenyl polyphosphates, cyclic adenosine 5'-diphosphoribose (cADPR) derivatives, and adenosine 5'-diphosphoribose (ADPR) analogues.
  • Biochemical assays to determine receptor binding and activation (e.g., IP3R, RyR).
  • Functional assays to measure Ca2+ release and channel activity (e.g., TRPM2).
  • In vitro and in vivo studies to evaluate the efficacy of synthetic analogues in disease models.

Main Results:

  • Synthetic AdA analogues provided a binding model for inositol 1,4,5-trisphosphate receptor (IP3R) activation.
  • Modified IP3 derivatives revealed conformational changes in the IP3R.
  • Biphenyl polyphosphates demonstrated the potential of non-inositol surrogates as IP3R modulators.
  • Stable cADPR analogues enabled investigation of ryanodine receptor (RyR)-mediated Ca2+ release.
  • Neutral analogues with pyrophosphate bioisosteres showed Ca2+ releasing ability, suggesting new membrane-permeant tools.
  • Synthetic ADPR analogues established the first structure-activity relationship (SAR) for TRPM2 channel activation and identified functional antagonists.
  • A nicotinic acid-based analogue antagonized NAADP-mediated Ca2+ release and showed efficacy in vivo against heart arrhythmia and autoimmune disease.

Conclusions:

  • Synthetic chemistry provides powerful tools to dissect complex Ca2+ signaling pathways.
  • Novel analogues offer unprecedented insights into receptor function and ion channel activity.
  • Targeted small molecules derived from synthetic efforts hold significant therapeutic potential for various diseases.