Strategies to prolong the plasma residence time of peptide drugs

Peptides are an attractive class of molecules for the development of therapeutics because they combine unique properties such as high binding affinity, excellent target specificity, low toxicity and a relatively small mass. However, the short in vivo half-life of peptides which is typically only a few minutes had hampered the development of a larger number of peptide leads into drugs. The main reasons for the fast elimination of peptides from the circulation are enzymatic degradation and/or fast renal clearance. To prolong the half-life of peptides, their proteolytic stability can be improved by chemical modification strategies and the rate of clearance can be reduced by conjugating the peptides to molecules that prevent their elimination through the kidney. In this article we review the latter class of strategies that aims at prolonging the in vivo plasma residence time of peptides. Techniques including peptide drug linkage to large polymers, fusion to long-lived proteins such as albumin or the Fc fragment of immunoglobulin and conjugation to small molecule albumin-binding tags are discussed and the peptide-conjugate half-lives achieved are compared.