Insights Into Receptor Function And New Drug Development Targets

We are now on the verge of viewing effector molecules and other regulatory sites as therapeutic targets for the amelioration of human and animal disease. The recognition, for example, that mutant proteins are frequently misrouted molecules, rather than functionally defective ones, changes our approach to "inborn errors of metabolism" and offers new approaches for pharmacological discovery, based on rescue of receptors, ion channels and enzymes with pharmacoperones. Ion channels, regulators of G-protein signaling and enzymes engaged in regulation, now present opportunities for drug development.

The state of our art also benefits by the availability of superior tools that allow measurement of interactions and afford unprecedented insight into the biomolecular interactions that present novel approaches to drug design.

G-Protein Coupled receptors (GPCRs) and other receptors are significant targets for drug discovery, due to their roles in fundamental physiological processes. Among these roles are: regulation of growth, food intake, reproduction, water balance, sensory perception, blood pressure and heart rate. GPCR-directed drugs account for approximately $40 billion in sales and, of drugs at market, approximately 70% target GPCR function.

The availability of combinatorial chemistry coupled with high throughput screening techniques have facilitated discovery of peptidic and non-peptidic ligands of membrane receptors. Mutant receptor models have revealed their role in health and disease and provided insight to new therapeutic approaches, based on control of protein trafficking. Understanding receptor-receptor interactions has provided one mechanism for receptor cross-talk and revealed unexpected interactions.

The completion of the human genome has identified a new source of therapeutic targets: "orphan receptors" with unknown functions and yet-to-be discovered ligands. Some orphans have now been identified as ghrelin, nociceptin, apelin, and urocortin. This finding, along with important technologies to develop ligands with desirable characteristics, including peptidomimetics is likely to further accelerate interest in this area.