Orally Active Peptides: Is There a Magic Bullet?
- 26 October 2018
- journal article
- review article
- Published by Wiley in Angewandte Chemie-International Edition
- Vol. 57 (44), 14414-14438
- https://doi.org/10.1002/anie.201807298
Abstract
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.Keywords
Funding Information
- Deutsche Forschungsgemeinschaft (Ke 147/42-1, CIPSM)
This publication has 186 references indexed in Scilit:
- The Role of BCS (Biopharmaceutics Classification System) and BDDCS (Biopharmaceutics Drug Disposition Classification System) in Drug DevelopmentJournal of Pharmaceutical Sciences, 2013
- Predicting and Improving the Membrane Permeability of Peptidic Small MoleculesJournal of Medicinal Chemistry, 2012
- Improving Metabolic Stability by Glycosylation: Bifunctional Peptide Derivatives That Are Opioid Receptor Agonists and Neurokinin 1 Receptor AntagonistsJournal of Medicinal Chemistry, 2009
- Probing the Bioactive Conformation of an Archetypal Natural Product HDAC Inhibitor with Conformationally Homogeneous Triazole‐Modified Cyclic TetrapeptidesAngewandte Chemie-International Edition, 2009
- Structural Requirements for a Lipoamino Acid in Modulating the Anticonvulsant Activities of Systemically Active Galanin AnaloguesJournal of Medicinal Chemistry, 2009
- ABCG2: A perspectiveAdvanced Drug Delivery Reviews, 2008
- High-throughput evaluation of relative cell permeability between peptoids and peptidesBioorganic & Medicinal Chemistry, 2008
- Synthesis and in vitro evaluation of a library of modified endomorphin 1 peptidesBioorganic & Medicinal Chemistry, 2008
- Structure‐activity relationship and metabolic stability studies of backbone cyclization and N‐methylation of melanocortin peptidesPeptide Science, 2008
- Quantitative Evaluation of the Relative Cell Permeability of Peptoids and PeptidesJournal of the American Chemical Society, 2007