Dual activation of TMEM16A and TRPV4 by EACT: A novel therapeutic strategy for cystic fibrosis

Cystic fibrosis (CF) is a chronic, progressive, and often fatal genetic disease primarily affecting the respiratory systems of children. The loss of CFTR function in CF results in airway surface dehydration and impaired mucociliary clearance. While no cure exists for CF, several treatments can alleviate symptoms and slow disease progression. This study examines Eact, a compound with the potential to offer a novel therapeutic approach for CF. Eact is known to activate TMEM16A (ANO1), a calcium-activated chloride channel (CaCC). Recent findings indicate that Eact also activates the Ca²⁺– permeable TRPV4 channel, which is essential for mucociliary clearance in ciliated epithelia and has multiple effects on CF pathogenesis. Our research aims to characterize the binding of Eact at the TRPV4 and TMEM16A channels using molecular docking simulations. The binding energy for TRPV4 with Eact was -5.9 kcal/mol, compared to -6.0 kcal/mol for TMEM16A with EACT, indicating comparable binding affinities. This dual activation capability suggests that Eact might influence multiple channels involved in CF’s pulmonary manifestations. By targeting both TMEM16A and TRPV4 channels, Eact emerges as a promising “2-in-1” compound for CF treatment. This study provides new insights into the therapeutic potential of Eact, highlighting its dual mechanism of action as a significant step toward developing more effective treatments for cystic fibrosis.