CHAPTER 7. Peptide Lead Optimization—Strategies and Tactics

Optimization of a lead peptide for drug development involves balancing activity at the target of interest and imparting acceptable pharmacokinetic properties so that the peptide can reach its target in vivo in sufficient concentration to obtain the desired pharmacological effects. After a brief review of the ADME (absorption, distribution, metabolism and excretion) issues in peptide drug development and classical approaches to lead peptide optimization, this chapter discusses newer approaches to peptide structural modification, including d-peptides, incorporation of β-amino acids, and additional cyclization strategies (ring closing metathesis, intramolecular “click” chemistry, and macrocyclic peptides), with recent examples from the literature and an emphasis on what is known about how structural modifications affect peptide pharmacokinetic properties.