Towards the Development of Orally Available Peptide Therapeutics.

Xu-Dong Kong,Christian Heinis

doi:10.2533/chimia.2021.514

Abstract

Peptides have a number of attractive properties that make them an interesting modality for drug development, including their ability to bind challenging targets, their high target specificity, and their non-toxic metabolic products. However, a major limitation of peptides as drugs is their typically poor oral availability, hindering their convenient and flexible application as pills. Of the more than 60 approved peptide drugs, the large majority is not orally applicable. The oral delivery of peptides is hampered by their metabolic instability and/or limited intestinal uptake. In this article, we review the barriers peptides need to overcome after their oral administration to reach disease targets, we highlight two recent successes of pharma companies in developing orally applicable peptide drugs, and we discuss efforts of our laboratory towards the generation of bioavailable cyclic peptides.

Highlights

Peptides have a number of attractive properties that make them an interesting modality for drug development, including their ability to bind challenging targets, their high target specificity, and their non-toxic metabolic products
We review the barriers peptides need to overcome after their oral administration to reach disease targets, we highlight two recent successes of pharma companies in developing orally applicable peptide drugs, and we discuss efforts of our laboratory towards the generation of bioavailable cyclic peptides
Attractiveness of Peptides as Therapeutics Peptides combine a number of qualities that make them an attractive modality for drug development

Summary

Recent Successes in the Development of Oral Peptide Drugs

Extensive efforts have been made to convert therapeutically active peptides into orally available drugs. Peptides are engineered for stability by altering the amino acid sequence eliminating vulnerable sites, by cyclizing or stapling to impose conformational constrains onto the backbone and hindering access of proteases, or by overall reducing the peptidic nature by replacing amino acids and peptide bonds by other chemical groups and linkages. It is chemically similar to GLP-1 but has modifications that prevent breakdown by dipeptidyl peptidase-4 and prolong the half-life through albumin binding It was initially developed and approved as a once-weekly injectable drug for type 2 diabetes, and was recently developed further for oral delivery through formulation in a tablet containing the permeation enhancer salcaprozate sodium (SNAC). In 2019, the oral semaglutide was approved for controlling blood sugar in adult patients with type 2 diabetes, and represents a landmark in the development of oral peptide therapeutics

In vitro Evolution of Peptides that Resist Gastrointestinal Proteolysis

High-throughput Screening of Sub-kilodalton Cyclic Peptides