Strategies to Optimize Peptide Stability and Prolong Half-Life

Peptide drugs represent 5% of the global pharmaceutical market, but growing twice as fast as the rest of the drug market. The development of peptide therapeutics is challenging due to their low stability, short half-life, and poor oral bioavailability. However, peptides typically have exquisite potency, selectivity, and low toxicity, making them particularly attractive for certain disease targets. Significant technological innovations have enabled the rapid advancement of peptide therapeutics to the clinic. Here, strategies to improve peptide proteolytic stability and prolong half-life are discussed. Structural modifications are highly effective for enhancing peptide stability, including replacing the natural L-amino acids with D- or unnatural amino acids, peptide backbone modifications, protecting N- and C-termini, and cyclization. In vitro and in vivo assays are available to assess peptide stability and develop structure-stability relationships to enable the design of more stable peptides. Peptides will continue to play an important role in filling the gaps between small molecule drugs and protein therapeutics.