Trends in Peptide Therapeutics

Abstract

The growing importance of peptide drugs within the pharmacopoeia has become evident over the past several decades. Among the factors that have contributed to this trend is the recognition that peptide ligands regulate a multitude of physiological pathways and are often suitable for therapeutic applications, in either their native or modified form. In addition, certain attributes that are unique to peptides, such as their high selectivity, potency, and lack of toxicity, have ultimately become appreciated. The alternative means of drugging peptide receptors through target‐directed screening or rational design of orally available small molecules have, with few exceptions, proved unproductive. Mimicking the activity of a peptide agonist is highly challenging, particularly in the case of Class II G‐protein‐coupled receptor (GPCR) targets. Successful examples have typically involved receptor antagonists such as neurokinin, angiotensin, endothelin, and orexin. These lessons have increasingly led drug discovery scientists to consider peptides as legitimate drug candidates, rather than leads or proof‐of‐concept models for small‐molecule programs. Peptide medicinal chemists have also had to confront and overcome shortcomings such as rapid metabolism, clearance, production costs, and limited alternative delivery options. In the present chapter, we highlight the role of peptides in therapeutic areas such as metabolic disease, where peptides have been well established, as well as in areas where their impact has been minor, but now rapidly expanding. We also emphasize examples where time‐extension strategies and alternative delivery routes have helped establish and strengthen the position of peptide drugs in competitive markets. Finally, we explore two novel trends in peptide drug discovery, macrocyclic and cell‐penetrating peptides, both of which may expand future opportunities for peptide therapeutics. Trends in Peptide Therapeutics Florence M. Brunel, Fa Liu, and John P. Mayer