ArticleProceedings of the National Academy of Sciences of the United States of America2022
Structural basis of peptidomimetic agonism revealed by small- molecule GLP-1R agonists Boc5 and WB4-24.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
16 citing papers in PubMed, 33 citations in OpenAlex.
- Orforglipron: A Comprehensive Review of an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity and Type 2 Diabetes.International journal of molecular sciences · 2026Review
- From Phytochemistry to Metabolic Regulation: The Insulin-Promoting Effects of Loureirin B Analogous to an Agonist of GLP-1 Receptor.International journal of molecular sciences · 2025Article
- Small-Molecule GLP-1 Receptor Agonists: A Promising Pharmacological Approach.Medicina (Kaunas, Lithuania) · 2025Review
- Oral delivery of GLP-1 peptide using recombinantMicrobiology spectrum · 2025Article
- Peptide Drug: Design and Clinical Applications.MedComm · 2025Review
- Hidden GPCR structural transitions addressed by multiple walker supervised molecular dynamics (mwSuMD).eLife · 2025Article
- Design, Structure-Activity Relationships, and Computational Modeling Studies of a Series of α-Helix Biased, Ultra-Short Glucagon-like Peptide-1 Receptor Agonists.Molecules (Basel, Switzerland) · 2024Article
- Sarcopenia-related changes in serum GLP-1 level affect myogenic differentiation.Journal of cachexia, sarcopenia and muscle · 2024Article
- Cryo-electron microscopy for GPCR research and drug discovery in endocrinology and metabolism.Nature reviews. Endocrinology · 2024Review
- G protein-coupled receptors (GPCRs): advances in structures, mechanisms, and drug discovery.Signal transduction and targeted therapy · 2024Review
- Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with GCell discovery · 2024Article
- Article
- Structural analysis of the dual agonism at GLP-1R and GCGR.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- New Insights into the Structure and Function of Class B1 GPCRs.Endocrine reviews · 2023Article
- GLP-1R Signaling and Functional Molecules in Incretin Therapy.Molecules (Basel, Switzerland) · 2023Review
- Deciphering the conformational landscape of few selected aromatic noncoded amino acids (NCAAs) for applications in rational design of peptide therapeutics.Amino acids · 2022Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective in treating type 2 diabetes and obesity with proven cardiovascular benefits. However, most of these agonists are peptides and require subcutaneous injection except for orally available semaglutide. Boc5 was identified as the first orthosteric nonpeptidic agonist of GLP-1R that mimics a broad spectrum of bioactivities of GLP-1 in vitro and in vivo. Here, we report the cryoelectron microscopy structures of Boc5 and its analog WB4-24 in complex with the human GLP-1R and Gs protein. Bound to the extracellular domain, extracellular loop 2, and transmembrane (TM) helices 1, 2, 3, and 7, one arm of both compounds was inserted deeply into the bottom of the orthosteric binding pocket that is usually accessible by peptidic agonists, thereby partially overlapping with the residues A8 to D15 in GLP-1. The other three arms, meanwhile, extended to the TM1-TM7, TM1-TM2, and TM2-TM3 clefts, showing an interaction feature substantially similar to the previously known small-molecule agonist LY3502970. Such a unique binding mode creates a distinct conformation that confers both peptidomimetic agonism and biased signaling induced by nonpeptidic modulators at GLP-1R. Further, the conformational difference between Boc5 and WB4-24, two closed related compounds, provides a structural framework for fine-tuning of pharmacological efficacy in the development of future small-molecule therapeutics targeting GLP-1R.
Indexed as
Identifiers
What Socratic holds
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 Socratic graph.