CHAPTER 2: Identification and Validation of Peptide Therapeutic Targets and Indications

Because peptide drug candidates are typically effective, potent and safer than small molecules, they are less susceptible to attrition during development. The market size for biologics, including peptides, is growing faster than for small molecules. Peptides address only two of the six major classes of drug target; primarily the (seven-transmembrane domain) G-protein coupled receptors, and secondarily the (single transmembrane domain) catalytic receptors. Since 86% of the currently marketed peptide drugs address only 4% of cell surface drug targets, peptides are likely underexploited as therapeutics. Discovery of therapeutic utility is a major gatekeeper to exploitation of peptide drugs. Several approaches are described: (1) derivation of “evolved purpose” from a sufficiently complete body of knowledge; (2) inference of function from anatomic distribution of targets; (3) observation of changes following signal interruption (knockouts, antagonists, and neutralizing antibodies); (4) observation of responses to supra-physiologic signal addition, progressing to physiologic signal addition. The usefulness of assays to identify biologic function generally increases with the complexity of the assay system, up to highly instrumented in vivo systems. The complexity of an assay typically correlates inversely with its throughput. Disease models, used with appropriate caution, can mitigate the risk and cost preceding clinical proof of concept studies of novel therapeutic hypotheses.