'Click cyclic ADP-ribose': a neutral second messenger mimic.

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Molecular Pharmacology

Background:

• Cyclic ADP-ribose (cADPR) is a crucial second messenger regulating intracellular calcium (Ca2+) release.
• Dysregulation of cADPR signaling is implicated in various diseases.
• Developing stable cADPR analogues is essential for therapeutic intervention.

Purpose of the Study:

• To synthesize novel cADPR analogues incorporating a 1,2,3-triazole pyrophosphate bioisostere.
• To evaluate the ability of these analogues to modulate Ca2+ signaling pathways.
• To assess the potential of these compounds as inhibitors of CD38, an enzyme that metabolizes cADPR.

Main Methods:

• Synthesis of cADPR analogues via click-mediated macrocyclization.
• Assay of Ca2+ release activation by the synthesized analogues.
• Enzyme inhibition assays using CD38 and the novel cADPR analogues.

Main Results:

• Successful synthesis of cADPR analogues featuring a 1,2,3-triazole pyrophosphate bioisostere.
• The synthesized analogues demonstrated retained potency in activating Ca2+ release.
• Significant inhibition of cADPR hydrolysis by CD38 was observed with the new analogues.

Conclusions:

• The 1,2,3-triazole pyrophosphate bioisostere is a viable strategy for designing stable cADPR analogues.
• These novel analogues hold promise as modulators of Ca2+ signaling pathways.
• The findings highlight the potential for developing drug-like molecules targeting cADPR-mediated signaling.