Cromolyn as a novel pharmacophore of the Zα domain of the RNA-editing enzyme ADAR1p150.

ADAR1p150 is a critical RNA-editing enzyme for maintaining cellular homeostasis through dsRNA binding, protein-protein interactions, and adenosine-to-inosine (A-to-I) editing. Beyond its dsRNA binding domains, ADAR1p150 contains a Zα domain that can induce a conformational switch of dsDNA and dsRNA from stable B/A forms to a higher-energy left-handed Z form. By stabilizing Z-RNA, ADAR1p150 is thought to modulate immune activation by competing with dsRNA sensors like MDA5 and ZBP1. ADAR1p150's editing activity minimizes dsRNA's presence and prevents dsRNA-mediated inflammatory pathways' activation. Our study employs NMR to introduce a novel pharmacophore model for Zα domain binders. We identify cromoglicic acid, also known as the FDA-approved drug cromolyn, as an ADAR1 Zα binder that competes with nucleic acid recognition. Cromolyn does not bind to ZBP1 Zα domains, which are the only other human Zα domains. Our work paves the way for effectively modulating ADAR1p150 function with small molecules, opening new avenues for enhancing anti-cancer immune responses.