Chloride Channelopathies: Translating Mechanistic Insights into Targeted Therapies

Pharmacology has a cation bias. For too long, research has focused heavily on sodium and potassium channels, often treating anion transport as a secondary concern. The breakthrough with CFTR modulators in Cystic Fibrosis proved this perspective is outdated; chloride channels are not just support players-they are highly viable targets for precision medicine. Yet, outside of CF, our therapeutic arsenal remains weak. We have practically no specific activators or inhibitors for major components of families like the CLCs, Bestrophins, and Anoctamins. The science is currently unbalanced. We have excellent genetic maps for conditions like myotonia congenita, Dent’s disease, and Bartter syndrome, Scott syndrome and the involvement of chloride channels in hypertension, pulmonary diseases, pain, and possibly cancer but we lack the molecular tools to treat them. This collection aims to fix that disconnect. We are not looking for generic phenotypic screening. We want studies that leverage structural biology and gating kinetics to drive rational drug design.We are calling for original research and reviews that rigorously address the molecular pharmacology of chloride channels.Priority will be given to manuscripts covering:• Structure-based design: Utilizing cryo-EM data of CLC or TMEM16/ANO proteins to map out new binding pockets.• Fixing the defect: Mechanisms of correctors and potentiators that solve trafficking or gating issues in non-CFTR diseases.• Smart repurposing: Identifying approved drugs that have overlooked effects on chloride conductance.• Subtype selectivity: Novel synthetic ligands or natural products that can finally distinguish between closely related isoforms (e.g., CLC-1 vs. CLC-2) an..d that bind specifically to the channel of interest (for example directly to ANO1 and not to proteins involved in calcium release, such as SERCA).• Patient-specific validation: The use of iPSC models or organoids to test pharmacological interventions in a translational context.Important note: Please note that submissions lacking experimental validation of in silico findings will not be considered. Topic editors: Michele Genovese, Frederic Becq, Jean-François Desaphy, Giulia Maria Camerino Source: https://www.frontiersin.org/research-topics/79453/chloride-channelopathies-translating-mechanistic-insights-into-targeted-therapies