Drug discovery and epithelial physiology

Small-molecule inhibitors and activators of gene products or cell functions can be valuable research tools for analyzing gene function ('chemical genetics'), and as leads for the development of new therapies ('drug discovery'). The recent National Institutes of Health roadmap highlights small-molecule discovery and applications in cellular and in-vivo systems as an important new research direction. The purpose of this review is to explain the small-molecule discovery process for investigators doing research in an academic setting, with emphasis on advances and directions in epithelial transport physiology.

The small-molecule discovery process involves the identification and validation of gene or phenotype targets, the screening of collections of small compounds for activity against the target, and the evaluation and optimization of compounds of interest. Many potential targets in renal epithelial physiology are suitable for small-molecule identification. Although small-molecule discovery in epithelial biology is in its infancy, recent advances have been reported in modulating the function of epithelial chloride channels, including the cystic fibrosis transmembrane conductance regulator and ClC-type chloride channels.

Small-molecule discovery by the screening of chemical libraries is feasible in the academic setting, and holds great potential for the elucidation of gene function and complex regulatory pathways, and the identification of lead drug candidates for rare diseases and diseases of limited commercial interest. The rapid chemical turn-off of gene function addresses the concerns of compensatory/developmental changes in cell and animal models of gene deletion.