Recent breakthroughs and future directions in drugging aquaporins

Abstract

Aquaporins are attractive targets for therapeutic intervention in the diverse conditions associated with water and solute dyshomeostasis that affect millions of patients worldwide every year. Aquaporin drug discovery has made little progress, possibly due to a range of assumptions including the intrinsic non-druggability of the aquaporin pore, compounded by issues with the reproducibility of current assays. We challenge the persistent idea that aquaporins are not druggable; the field is still in its infancy and much progress is yet to be made. Viable routes to inhibition of aquaporin function have recently been identified, including targeting their regulation as well as their pores. Identifying new aquaporin-targeted drugs for conditions associated with disrupted water and solute homeostasis will meet an urgent, unmet clinical need as no pharmacological interventions are currently available. Inhibition of hydrogen peroxide permeation through AQP1 provides a new approach to treating hypertrophic cardiomyopathies. Inhibition of AQP4 localization with the licensed drug trifluoperazine provides compelling evidence for a new approach to treating CNS edema.