Peptide Therapeutics and Next Generation Drug Delivery Systems

Emerging Frontiers in Drug Discovery and Medicinal Chemistry

Abstract

Peptide based therapeutics occupy a distinctive middle ground between small molecule drugs and large biologics, combining the target specificity and low off-target toxicity characteristic of proteins with a synthetic tractability that has made them an increasingly attractive drug class. Seven of the ten best-selling pharmaceuticals worldwide are now based on amino acid sequences, reflecting the clinical and commercial maturation of this modality. Yet the same physicochemical properties that confer peptides their selectivity, namely their size, conformational flexibility, and susceptibility to proteolytic degradation, also render them vulnerable to rapid enzymatic breakdown and poor membrane permeability, historically restricting most peptide drugs to parenteral administration. This review surveys the structural and physiological barriers that limit peptide bioavailability, summarizes the principal chemical and formulation strategies developed to overcome them, including chemical modification, permeation enhancers, and lipid-based nanoparticulate carriers, and evaluates the clinical translation of oral peptide delivery through the case study of oral semaglutide. We conclude by considering the formulation and regulatory trends likely to shape the next generation of peptide therapeutics.