Improving on nature : making a cyclic heptapeptide orally bioavailable
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim..
The use of peptides in medicine is limited by low membrane permeability, metabolic instability, high clearance, and negligible oral bioavailability. The prediction of oral bioavailability of drugs relies on physicochemical properties that favor passive permeability and oxidative metabolic stability, but these may not be useful for peptides. Here we investigate effects of heterocyclic constraints, intramolecular hydrogen bonds, and side chains on the oral bioavailability of cyclic heptapeptides. NMR-derived structures, amide H-D exchange rates, and temperature-dependent chemical shifts showed that the combination of rigidification, stronger hydrogen bonds, and solvent shielding by branched side chains enhances the oral bioavailability of cyclic heptapeptides in rats without the need for N-methylation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2014 |
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| Erschienen: |
2014 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:53 |
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| Enthalten in: |
Angewandte Chemie (International ed. in English) - 53(2014), 45 vom: 03. Nov., Seite 12059-63 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Nielsen, Daniel S [VerfasserIn] |
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| Links: |
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| Themen: |
Cyclic peptides |
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| Anmerkungen: |
Date Completed 23.06.2015 Date Revised 16.03.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/anie.201405364 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 500 | |a Date Revised 16.03.2022 | ||
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. | ||
| 520 | |a The use of peptides in medicine is limited by low membrane permeability, metabolic instability, high clearance, and negligible oral bioavailability. The prediction of oral bioavailability of drugs relies on physicochemical properties that favor passive permeability and oxidative metabolic stability, but these may not be useful for peptides. Here we investigate effects of heterocyclic constraints, intramolecular hydrogen bonds, and side chains on the oral bioavailability of cyclic heptapeptides. NMR-derived structures, amide H-D exchange rates, and temperature-dependent chemical shifts showed that the combination of rigidification, stronger hydrogen bonds, and solvent shielding by branched side chains enhances the oral bioavailability of cyclic heptapeptides in rats without the need for N-methylation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a NMR | |
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| 650 | 4 | |a oral bioavailability | |
| 650 | 4 | |a permeability | |
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| 650 | 7 | |a Peptides, Cyclic |2 NLM | |
| 700 | 1 | |a Hoang, Huy N |e verfasserin |4 aut | |
| 700 | 1 | |a Lohman, Rink-Jan |e verfasserin |4 aut | |
| 700 | 1 | |a Hill, Timothy A |e verfasserin |4 aut | |
| 700 | 1 | |a Lucke, Andrew J |e verfasserin |4 aut | |
| 700 | 1 | |a Craik, David J |e verfasserin |4 aut | |
| 700 | 1 | |a Edmonds, David J |e verfasserin |4 aut | |
| 700 | 1 | |a Griffith, David A |e verfasserin |4 aut | |
| 700 | 1 | |a Rotter, Charles J |e verfasserin |4 aut | |
| 700 | 1 | |a Ruggeri, Roger B |e verfasserin |4 aut | |
| 700 | 1 | |a Price, David A |e verfasserin |4 aut | |
| 700 | 1 | |a Liras, Spiros |e verfasserin |4 aut | |
| 700 | 1 | |a Fairlie, David P |e verfasserin |4 aut | |
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