Basic Concepts of Design of Peptide-Based Therapeutics

Abstract

Peptides are natural ligands for numerous receptors in the human body, and many of these, such as hormones, neurotransmitters, and growth factors, have physiological roles. Peptides are highly selective and relatively well tolerated in the human body. More than 80 peptide-based drugs approved by the FDA are now on the market. A major challenge in peptide-based therapeutics is in vivo stability of peptides for oral administration. There have been several attempts to increase the enzymatic stability of peptides using backbone or side-chain modification. These methods include cyclization, stapled peptide approach, and N-methylation, in addition to grafting peptides to cyclic peptide or cyclotide frameworks. Peptide therapeutics gained momentum during the last decade as the three-dimensional structures of many proteins were elucidated. The functions of these proteins and their relevance in the biochemical pathways of diseases were revealed. In this chapter, the fundamentals of peptide-based drug design are covered, with an emphasis on the structural biology aspects of peptide drug design. Four examples, namely, the design of an angiotensin-converting enzyme inhibitor; an RGD peptide cilengitide; the use of a naturally occurring peptide, polymyxin; and, finally, a relatively new area in peptide-based drug design, protein-protein interaction inhibitors, are described.