Structure-guided design of picomolar-level macrocyclic TRPC5 channel inhibitors with antidepressant activity.

ABSTRACT: Recent advances in ion channel structural biology have enhanced structure-based drug design, yet lipid-occupied binding pockets-often large and flat-remain a major hurdle for developing selective small molecules. TRPC5, a brain-enriched channel regulating depression and anxiety, is a promising therapeutic target, but current preclinical candidates suffer from moderate off-target effects. To address this, we designed macrocyclic TRPC5 inhibitors using structure-guided macrocyclization, overcoming lipid-binding site challenges. Among these, JDIC-127 exhibited unprecedented potency with IC₅₀ of 374 pmol/L-200-fold more potent than HC-070-and exceptional selectivity. Its specificity arises from interactions with unique structural features near the S5 and S6 helices of TRPC5, minimiz

SUBMITTER: Che T 

PROVIDER: S-EPMC12827894 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature