Advances in oral peptide therapeutics

Abstract

Protein and peptide therapeutics require parenteral administration, which can be a deterrent to medication adherence. For this reason, there have been extensive efforts to develop alternative delivery strategies, particularly for peptides such as insulin that are used to treat endocrine disorders. Oral delivery is especially desirable, but it faces substantial barriers related to the structural organization and physiological function of the gastrointestinal tract. This article highlights strategies designed to overcome these barriers, including permeation enhancers, inhibitors of gut enzymes, and mucus-penetrating and cell-penetrating peptides. It then focuses on the experience with oral peptides that have reached clinical trials, including insulin, calcitonin, parathyroid hormone and vasopressin, with an emphasis on the advances that have recently led to the landmark approval of an oral formulation of the glucagon-like peptide 1 receptor agonist semaglutide for the treatment of type 2 diabetes.

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Fig. 1: Schematic representation of intestinal structure and the associated challenges to efficient oral absorption of peptides.
Fig. 2: Technologies that have been applied for gastrointestinal peptide absorption in different regions of the gastrointestinal tract.
Fig. 3: Absorption of oral semaglutide.

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Acknowledgements

D.J.D. is supported in part by a Banting and Best Diabetes Centre Novo Nordisk Chair in Incretin Biology, by CIHR Foundation Grant 154321 and by investigator-initiated operating grants for preclinical GLP1 science from Novo Nordisk.

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Correspondence to Daniel J. Drucker.

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D.J.D. has served as an adviser or consultant or speaker within the past 12 months to Forkhead Biotherapeutics, Heliome Inc., Intarcia Therapeutics, Kallyope, Merck Research Laboratories, Novo Nordisk Inc., Pfizer Inc. and Sanofi Inc. Neither D.J.D. nor his family members hold stock directly or indirectly in any of these companies. GLP2 is the subject of a patent licence agreement between Shire Inc. and the University of Toronto, Toronto General Hospital (UHN) and D.J.D.

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Drucker, D.J. Advances in oral peptide therapeutics. Nat Rev Drug Discov 19, 277–289 (2020). https://doi.org/10.1038/s41573-019-0053-0

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