ArticleJournal of the American Chemical Society2017
Thioamide Substitution Selectively Modulates Proteolysis and Receptor Activity of Therapeutic Peptide Hormones.
Article in Journal of the American Chemical Society, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 101 citations in OpenAlex.
- Potent and biased agonists of class B1 GPCRs from a heterochiral design strategy.Nature chemistry · 2026Article
- Thioimidate Protection Enables Amide, Thioamide, and Amidine Installation at Aspartic Acid Residues.The Journal of organic chemistry · 2026Article
- Advancing protein engineering via organic chemistry.Communications chemistry · 2026Review
- Programmable Helicity and Macrocycle Symmetry in β-Peptides via Site-Selective Thioamide Substitution.Journal of the American Chemical Society · 2025Article
- Chemical Engineering of Transcription Factors Uncovered Cell-Permeable μMax Modulators.Journal of the American Chemical Society · 2025Article
- Expanding the Chemical Space of Mechanically Interlocked Peptides (MIPs) via Rational Design and Metabolite Profiling.JACS Au · 2025Article
- Unexpected Reactivity of Nitrones: Catalytic Insertion of CSOrganic letters · 2025Article
- Potent and Protease Resistant Azapeptide Agonists of the GLP-1 and GIP Receptors.Angewandte Chemie (International ed. in English) · 2024Article
- Thioamides in medicinal chemistry and as small molecule therapeutic agents.European journal of medicinal chemistry · 2024Review
- Complementary Strategies for Installation of Thioimidates into Peptide Backbones.The Journal of organic chemistry · 2024Article
- Thioimidate Solutions to Thioamide Problems during Thionopeptide Deprotection.Organic letters · 2024Article
- Thioimidates provide general access to thioamide, amidine, and imidazolone peptide-bond isosteres.Methods in enzymology · 2024Article
- Thioamide Analogues of MHC I Antigen Peptides.Journal of the American Chemical Society · 2023Article
- Harnessing Aromatic-Histidine Interactions through Synergistic Backbone Extension and Side Chain Modification.Angewandte Chemie (International ed. in English) · 2023Article
- Structure-Activity Relationships of the Antimicrobial Peptide Natural Product Apidaecin.Journal of medicinal chemistry · 2023Article
- Novel Compounds Derived from DFPM Induce Root Growth Arrest through the SpecificLife (Basel, Switzerland) · 2023Article
- Nitroalkanes as thioacyl equivalents to access thioamides and thiopeptides.Nature communications · 2023Article
- Alternative Pharmacological Strategies for the Treatment of Alzheimer's Disease: Focus on Neuromodulator Function.Biomedicines · 2022Review
- Article
- On the Utility of Chemical Strategies to Improve Peptide Gut Stability.Journal of medicinal chemistry · 2022Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Peptide hormones are attractive as injectable therapeutics and imaging agents, but they often require extensive modification by mutagenesis and/or chemical synthesis to prevent rapid in vivo degradation. Alternatively, the single-atom, O-to-S modification of peptide backbone thioamidation has the potential to selectively perturb interactions with proteases while preserving interactions with other proteins, such as target receptors. Here, we use the validated diabetes therapeutic, glucagon-like peptide-1 (GLP-1), and the target of clinical investigation, gastric inhibitory polypeptide (GIP), as proof-of-principle peptides to demonstrate the value of thioamide substitution. In GLP-1 and GIP, a single thioamide near the scissile bond renders these peptides up to 750-fold more stable than the corresponding oxopeptides toward cleavage by dipeptidyl peptidase 4, the principal regulator of their in vivo stability. These stabilized analogues are nearly equipotent with their parent peptide in cyclic AMP activation assays, but the GLP-1 thiopeptides have much lower β-arrestin potency, making them novel agonists with altered signaling bias. Initial tests show that a thioamide GLP-1 analogue is biologically active in rats, with an in vivo potency for glycemic control surpassing that of native GLP-1. Taken together, these experiments demonstrate the potential for thioamides to modulate specific protein interactions to increase proteolytic stability or tune activation of different signaling pathways.
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Registered trials
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.