Design and synthesis of chemically modified peptides and proteins —critical considerations for oral delivery

Abstract

Naturally occurring polypeptides and proteins are recognized by digestive and circulatory enzymes which rapidly degrade and inactivate them. Even in the absence of degradation, the gastrointestinal tract presents a formidable physical barrier which precludes efficient absorption of all but the smallest oligopeptide fragments. In the event that assisted absorption can be effective, renal clearance from the systemic circulation quickly eliminates most unmodified peptides before they reach their target receptor. Here we discuss the barriers which exclude potential peptide therapeutics from peroral delivery and present some recent strategies in peptidomimetic design which have enabled just a handful of candidates to achieve regulatory approval by the oral route. The conclusion is that there are a specific set of physicochemical and biochemical properties which need to be fulfilled to achieve successful oral delivery of a peptide candidate and that meeting these criteria will not always be possible with all known endogenous peptides of interest.