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Metabolic
A peptidic triple-receptor agonist studied in metabolic and endocrinology research.
RT-10 is a lipidated synthetic peptide investigated across receptor pharmacology and metabolic research. It simultaneously engages three class B GPCR targets — the GLP-1, GIP, and glucagon receptors — and appears in in vitro signaling studies, animal metabolic models, and published multi-dose study design literature examining metabolic and hepatic biomarker endpoints.
Reviewed by Dr. James Whitfield, PharmD · Published · Last reviewed · For research use only.
Type
Synthetic peptide (acylated, 39 residues)
Molecular formula
C221H342N46O68
Molecular weight
~4,731 Da
CAS number
2381089-83-2
Amino acids
39
Fatty acid chain
C20 diacid
Modification
Aib at positions 2 and 20; α-methyl-Leu at position 13; C-terminal amide; Lys17-linked C20 fatty-diacid acylation via a γ-Glu/AEEA linker.
A single-peptide triple agonist built on a GIP/GLP-1/glucagon hybrid scaffold that engages three class B GPCRs — the GIP receptor (GIPR), the GLP-1 receptor (GLP-1R), and the glucagon receptor (GCGR). Cryo-EM structures of RT-10 bound to each receptor–Gs complex reveal a continuous α-helical conformation in which the N-terminal segment inserts into the receptor's transmembrane bundle and the central segment contacts extracellular loops. Non-standard residues (Aib, α-methyl-Leu) confer protease resistance; the C20 fatty-diacid side chain confers reversible albumin binding, extending circulatory half-life.
Research Focus
Studied in vitro and in preclinical models in the context of receptor pharmacology and metabolic disease research.
In vitro studies characterize RT-10 as a full agonist at each of its three target receptors. Using cAMP accumulation assays in cells expressing GLP-1R, GIPR, and GCGR individually, investigators (Coskun et al., 2022) measured receptor activation and compared it with native reference ligands. Binding assays confirmed high-affinity engagement at each receptor. In primary human cell models carrying endogenous receptor expression, assays examined hepatocyte glucose output (via GCGR engagement) and adipocyte lipolysis (via GIPR engagement). Alanine-scanning mutagenesis, conducted alongside cryo-EM structural analysis, identified both shared and receptor-specific peptide–receptor contacts, providing a mechanistic basis for how a single peptide sequence can simultaneously activate three structurally homologous but pharmacologically distinct GPCRs. Downstream Gs signaling was confirmed at each receptor through cAMP pathway readouts.
Single-particle cryo-EM was used to resolve RT-10 in complex with each receptor–Gs system at near-atomic resolution. Li et al. (2024) determined structures of human GLP-1R–Gs, GIPR–Gs, and GCGR–Gs complexes bound to RT-10 at 2.68 Å, 3.26 Å, and 2.84 Å, respectively. In all three complexes, the peptide adopts a continuous α-helical conformation: the N-terminal segment inserts into the receptor's transmembrane bundle, while the central segment contacts extracellular loops and the N-terminal receptor helix. Structural comparison across the three complexes identified both conserved contacts — salt bridges and hydrophobic interactions with core transmembrane residues — and receptor-specific features: extracellular loop 1 of GCGR shifts to accommodate the peptide N-terminus, while the GIPR loop 1 configuration causes the bound peptide to adopt a slightly different helical geometry relative to GLP-1R and GCGR. These structural data establish at atomic resolution how a single peptide backbone can engage three homologous class B receptors and inform the rational design of subsequent multi-agonist ligands.
In rodent experiments, RT-10 has been examined in diet-induced rodent metabolic models and in wild-type versus receptor-knockout comparisons. Coskun et al. (2022) used receptor-specific knockout mice to assess the contribution of individual GLP-1R, GIPR, and GCGR engagement to glucose homeostasis and energy metabolism measurements. Studies conducted under high-fat diet conditions measured food intake, energy expenditure, and liver-histology readouts. Briand et al. (2025) assessed RT-10 in diet-induced MASH rodent models using metabolic endpoints. In human cell-based assays with endogenous receptor expression, glucose production in hepatocytes (GCGR-mediated) and lipolysis in adipocytes (GIPR-mediated) were measured; a validated protocol for the adipocyte lipolysis assay was published separately (Regmi and Roell, 2023). Marathe et al. (2025) examined the compound in a mouse cancer model. These preclinical experiments provided mechanistic data that have been cited in the published clinical pharmacology literature.
Urva et al. (2022) reported a Phase 1b multiple-cohort escalating-dose study assessing pharmacokinetic and pharmacodynamic markers; pharmacokinetic analysis characterized a multi-day terminal half-life profile that informed subsequent trial design. A further Phase 1 study (Urva et al., 2023) examined gastric emptying as a pharmacodynamic endpoint in enrolled study participants. These studies established the pharmacokinetic profile and escalation framework carried into larger multi-dose trials.
Phase 2 placebo-controlled studies have examined RT-10 across multiple dose groups, with metabolic, glycemic, and hepatic-imaging endpoints assessed over study periods up to 48 weeks; one Phase 2a study used MRI-quantified liver fat as its primary endpoint. These records are listed in the references for study-design context only, and systematic reviews and meta-analyses of the available Phase 2 data have also been published. No efficacy claims or clinical verdicts are drawn from them.
Giblin et al. (2026) described the rationale and design of a Phase 3 multi-trial program evaluating escalating dose regimens of RT-10 versus placebo across multiple confirmatory study designs. The design paper outlines enrollment criteria, dose-escalation structures, and endpoint selection across the planned confirmatory trials; outcome data from these studies are not yet published. A review by Gutgesell et al. (2024) situates RT-10 within the broader class of dual and triple incretin receptor agonists in metabolic disease research, providing context for the compound's place in the evolving landscape of multi-agonist peptide pharmacology.
Lyophilized
-20°C (-80°C long term)
powder typically stable ~24 months.
Reconstituted
-20°C ~1 month
2-8°C for short-term working use only.
Aliquot to avoid freeze-thaw; protect from light; keep sealed and dry.
Reviews
Gutgesell RM, Nogueiras R, Tschöp MH, Müller TD. (2024). Diabetes Therapy — Review of dual and triple incretin receptor agonist therapies in metabolic research
Misra S, et al. (2025). J Basic Clin Physiol Pharmacol — Systematic review of RT-10 Phase 2 clinical study data
Systematic review & meta-analysis (2025). PubMed — Systematic review and meta-analysis of RT-10 multi-dose study data
Reviews
Pasqualotto E, et al. (2024). Metabolism Open — Systematic review and meta-analysis of RT-10
Doggrell SA. (2023). Expert Opin Investig Drugs — Review of RT-10 pharmacology and development
Kaur M, Misra S. (2024). Eur J Clin Pharmacol — Review of RT-10 triple-agonist pharmacology in metabolic research
Ray A. (2023). Expert Opin Investig Drugs — Review of RT-10 as a triple incretin receptor agonist
Tetelbaum L, Mullally JA, Frishman WH. (2024). Cardiol Rev — Review of RT-10 triple-agonist pharmacology in metabolic research
Sinha B, Ghosal S. (2025). Obesity (Silver Spring) — Bayesian network meta-analysis of incretin agonist classes including RT-10
Clinical
Coskun T, et al. (2025). Lancet Diabetes & Endocrinology — Phase 2 multi-dose substudy examining metabolic endpoints
Giblin K, et al. (2026). Diabetes, Obesity and Metabolism — Phase 3 multi-trial program design and rationale paper
Sanyal AJ, et al. (2024). Nature Medicine — Phase 2a randomized, placebo-controlled hepatic imaging study
Urva S, et al. (2023). Diabetes, Obesity and Metabolism — Study of RT-10 and gastric emptying
Rosenstock J, et al. (2023). The Lancet — Phase 2 randomized, placebo- and active-controlled multi-dose study
Jastreboff AM, et al. (2023). NEJM — Phase 2 randomized, placebo-controlled multi-dose study (NCT04881760)
Urva S, et al. (2022). The Lancet — Phase 1b multiple-cohort pharmacokinetic and pharmacodynamic study
Primary research
Briand F, et al. (2025). Obesity — Preclinical metabolic study of RT-10 in a diet-induced rodent metabolic model
Marathe SJ, et al. (2025). npj Metabolic Health and Disease — Preclinical study of RT-10 in a mouse cancer model
Li W, et al. (2024). Cell Discovery — Cryo-EM structural study of RT-10 bound to GLP-1R, GIPR, and GCGR
Regmi A, Roell W. (2023). STAR Protocols — In vitro adipocyte lipolysis protocol with RT-10
Coskun T, et al. (2022). Cell Metabolism — Discovery and translational characterization of RT-10 as a triple receptor agonist
Research Use Only
These products are intended for research purposes only and are not for human consumption. Not FDA approved. Not intended to diagnose, treat, cure, or prevent any disease.
| Compound | Type | Molecular weight | CAS number |
|---|---|---|---|
| RT-10This page | Synthetic peptide (acylated, 39 residues) | ~4,731 Da | 2381089-83-2 |
| GLP-1 (SM) | Synthetic peptide (acylated, 31 residues) | ~4,114 g/mol | 910463-68-2 |
| GLP-1 (TRZ) | Synthetic linear peptide (dual GLP-1R/GIPR agonist; acylated, 39 residues) | ~4,814 g/mol | 2023788-19-2 |
| AOD-9604 | Synthetic peptide (cyclic, 16 residues) | ~1,815 g/mol | 221231-10-3 |
| MOTS-c | Mitochondrial-derived peptide (16 residues) | ~2,175 g/mol | 1627580-64-6 |
Comparison of laboratory reference specifications only. For research use only; not a therapeutic comparison.
Quality & methods