Overcoming Challenges in the Metabolism of Peptide Therapeutics: Strategies and Case Studies for Clinical Success.

Peptide therapeutics are rapidly emerging as a new drug modality, bridging the gap between small molecules and biologics to target diseases such as diabetes, cancer, and cardiovascular disorders. Despite their advantages, challenges like metabolic instability, low permeability, and rapid clearance hinder their clinical development. This perspective focuses on addressing challenges in the metabolism of peptides by exploring key strategies including structural modifications (cyclization, incorporation of noncanonical amino acids, PEGylation, and lipidation) alongside advancements in delivery technologies (nanoparticles and protein conjugation). Low permeability and bioavailability of peptides are also briefly covered. Case studies, including semaglutide, MK-0616, LUNA18, sulanemadlin, and oxytocin analogs, illustrate successful applications of these strategies, highlighting how rational design and optimization have advanced peptide candidates from discovery to clinical stage.