Orally Active Peptides: Is There a Magic Bullet?

Andreas F.B. Räder, Michael Weinmüller, Florian Reichart, Adi Schumacher-Klinger, Shira Merzbach, Chaim Gilon, Amnon Hoffman, Horst Kessler*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

108 Scopus citations


For decades, the development of peptides as potential drugs was aimed solely at peptides with the highest affinity, receptor selectivity, or stability against enzymatic degradation. However, optimization of their oral availability is highly desirable to establish orally active peptides as potential drug candidates for everyday use. A twofold optimization process is necessary to produce orally active peptides: 1) optimization of the affinity and selectivity and 2) optimization of the oral availability. These two steps must be performed sequentially for the rational design of orally active peptides. Nevertheless, additional knowledge is required to understand which structural changes increase oral availability, followed by incorporation of these elements into a peptide without changing its other biological properties. Considerable efforts have been made to understand the influence of these modifications on oral availability. One approach is to improve the oral availability of a peptide that has been previously optimized for biological activity, as described in (1) above. The second approach is to first identify an intestinally permeable, metabolically stable peptide scaffold and then introduce the functional groups necessary for the desired biological function. Previous approaches to achieving peptide oral availability have been claimed to have general applicability but, thus far, most of these solutions have not been successful in other cases. This Review discusses diverse chemical modifications, model peptides optimized for bioavailability, and orally active peptides to summarize the state of the research on the oral activity of peptides. We explain why no simple and straightforward strategy (i.e. a “magic bullet”) exists for the design of an orally active peptide with a druglike biological function.

Original languageAmerican English
Pages (from-to)14414-14438
Number of pages25
JournalAngewandte Chemie - International Edition
Issue number44
StatePublished - 26 Oct 2018

Bibliographical note

Publisher Copyright:
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim


  • bioavailability
  • cyclization
  • drug design
  • oral activity
  • peptides


Dive into the research topics of 'Orally Active Peptides: Is There a Magic Bullet?'. Together they form a unique fingerprint.

Cite this