Epithelial plasma membrane transporters as drug targets

Small molecule discovery and drug development are increasingly being pursued in academic settings, expanding beyond their traditional confinement to the pharmaceutical industry. The initial steps in drug discovery typically include identification and validation of a target, screening of chemical libraries to identify modulators of target activity, and subsequent prioritization and optimization of lead compounds using in vitro systems and animal models, with emphasis on compound potency, selectivity and pharmacological properties. This review focuses on early-stage discovery of small molecules that target plasma membrane transporters on epithelial cells, including absorptive and secretory epithelia in kidney, gastrointestinal tract, lung and eye. Of the estimated 500 distinct epithelial plasma membrane transporters, fewer than a dozen are the targets of approved drugs, most of which have been in clinical use for decades. We discuss the logistics and challenges associated with small molecule discovery in an academic setting. Specific epithelial cell targets are considered, including chloride channels, solute-coupled transporters, urea transporters and aquaporins, with therapeutic implications spanning constipation and secretory diarrheas, cystic fibrosis, dry eye disease, edema, hypertension and kidney stones. We conclude by identifying unmet needs and outlining opportunities to enable next-generation pharmacological modulation of epithelial transport processes.