ArticleProceedings of the National Academy of Sciences of the United States of America2014
Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 167 citations in OpenAlex.
- The isolated Stachel peptide of the adhesion G protein-coupled receptor ADGRG6 is predominantly disordered with local helical propensity.Biophysical journal · 2026Article
- Backbone Steric Constraints Underlie High Passive Membrane Permeability of N-Alkyl Peptides.Angewandte Chemie (International ed. in English) · 2026Article
- Experimental Evidence for a Metal-Related Function of a Cyanobactin.Angewandte Chemie (International ed. in English) · 2026Article
- The isolatedbioRxiv : the preprint server for biology · 2026Article
- Backbone Alterations in Cyclic Peptides Influence Both Membrane Permeability and Biological Activity.Journal of medicinal chemistry · 2025Article
- Challenges of Aufheben to Promote Druglikeness: Chemical Modification Strategies to Improve Aqueous Solubility and Permeability.Journal of medicinal chemistry · 2025Review
- Systematic Determination of the Impact of Structural Edits on Peptide Accumulation into Mycobacteria.ACS chemical biology · 2025Article
- Solid-Phase Synthesis of Peptides with Methyl and Larger Substituents on Backbone Amide Nitrogens via On-Resin Incorporation of the Substituents.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Cyclic Peptide C5aR1 Antagonist Design Using Solution Conformational Analysis Derived from Residual Dipolar Couplings.ACS medicinal chemistry letters · 2024Article
- De Novo Synthesis and Structural Elucidation of CDR-H3 Loop Mimics.ACS chemical biology · 2024Article
- Beyond N-Alkylation: Synthesis, Structure, and Function of N-Amino Peptides.Accounts of chemical research · 2024Article
- De novo development of small cyclic peptides that are orally bioavailable.Nature chemical biology · 2024Article
- Cell penetration of oxadiazole-containing macrocycles.RSC chemical biology · 2024Article
- Discovery of Acyl-Surugamide A2 from MarineMolecules (Basel, Switzerland) · 2024Article
- Membrane Permeability in a Large Macrocyclic Peptide Driven by a Saddle-Shaped Conformation.Journal of the American Chemical Society · 2024Article
- Oral Absorption of Middle-to-Large Molecules and Its Improvement, with a Focus on New Modality Drugs.Pharmaceutics · 2023Review
- An amide to thioamide substitution improves the permeability and bioavailability of macrocyclic peptides.Nature communications · 2023Article
- Cell-permeable chameleonic peptides: Exploiting conformational dynamics in de novo cyclic peptide design.Current opinion in structural biology · 2023Review
- Amide-to-ester substitution as a stable alternative to N-methylation for increasing membrane permeability in cyclic peptides.Nature communications · 2023Article
- Each side chain of cyclosporin A is not essential for high passive permeability across lipid bilayers.RSC advances · 2023Article
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Enhancing the oral bioavailability of peptide drug leads is a major challenge in drug design. As such, methods to address this challenge are highly sought after by the pharmaceutical industry. Here, we propose a strategy to identify appropriate amides for N-methylation using temperature coefficients measured by NMR to identify exposed amides in cyclic peptides. N-methylation effectively caps these amides, modifying the overall solvation properties of the peptides and making them more membrane permeable. The approach for identifying sites for N-methylation is a rapid alternative to the elucidation of 3D structures of peptide drug leads, which has been a commonly used structure-guided approach in the past. Five leucine-rich peptide scaffolds are reported with selectively designed N-methylated derivatives. In vitro membrane permeability was assessed by parallel artificial membrane permeability assay and Caco-2 assay. The most promising N-methylated peptide was then tested in vivo. Here we report a novel peptide (15), which displayed an oral bioavailability of 33% in a rat model, thus validating the design approach. We show that this approach can also be used to explain the notable increase in oral bioavailability of a somatostatin analog.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.