Retatrutide (LY3437943)
Identification
| Property |
Value |
| Molecular Formula |
C₂₂₃H₃₄₃N₄₇O₆₈ |
| Molecular Weight |
~4,845.5 Da |
| Amino Acid Count |
39 |
| Appearance |
White to off-white lyophilized powder |
| Solubility |
Soluble in aqueous buffers; may require pH adjustment for complete dissolution |
| Receptor Targets |
GIPR / GLP-1R / GCGR (triple agonist) |
Structural & Pharmacological Profile
Retatrutide is an investigational triple-hormone-receptor agonist designed to activate the glucose-dependent insulinotropic polypeptide receptor (GIPR), glucagon-like peptide-1 receptor (GLP-1R), and glucagon receptor (GCGR). The peptide features a 39-amino acid backbone with structural modifications enabling balanced activity across all three receptors and an extended pharmacokinetic profile via a C20 fatty diacid-albumin binding mechanism.
Key Structural Features
| Feature |
Detail |
| Peptide Backbone |
39-amino acid single-chain peptide with targeted sequence modifications for triple receptor agonism |
| Fatty Acid Moiety |
C20 eicosanedioic acid |
| Linker Chemistry |
gamma-Glu-2xOEG spacer to Lys residue |
| Glucagon Activity |
Amino acid substitutions in the glucagon homology region provide balanced GCGR agonism without inducing hyperglycemia |
| Half-Life |
~6 days in preclinical models |
Comparator Analysis
| Parameter |
Semaglutide |
Tirzepatide |
Retatrutide |
| Receptor Target |
GLP-1R (selective) |
GIPR / GLP-1R (dual) |
GIPR / GLP-1R / GCGR (triple) |
| Molecular Weight |
~4,113.6 Da |
~4,813.5 Da |
~4,845.5 Da |
| Amino Acid Count |
31 |
39 |
39 |
| Clinical BW Reduction |
~14.9% (68 wk) |
~22.5% (72 wk) |
~24.2% (Phase 2, 48 wk) |
| Half-Life |
~7 days |
~5 days |
~6 days |
| Synthesis Complexity |
High |
Very High |
Complex |
| GCGR Activity |
None |
None |
Yes |
| Fatty Acid Linker |
C18 fatty diacid |
C20 fatty diacid |
C20 fatty diacid |
Clinical data cited from published trial results in peer-reviewed literature. Phase 2 data for retatrutide is from a 48-week dose-ranging study; Phase 3 outcomes may differ.
Research Applications
| Research Domain |
Description |
| Body Weight & Energy Expenditure |
GCGR activation increases energy expenditure and lipid oxidation, complementing the anorectic effects of GLP-1R and GIPR agonism |
| Glucose Homeostasis |
Balanced triple agonism provides GIPR-mediated insulin secretion, GLP-1R-mediated glucose-dependent insulin potentiation, and GCGR-mediated hepatic glucose output modulation |
| Hepatic Lipid Metabolism |
GCGR component increases hepatic fatty acid oxidation; reduced liver fat content observed in Phase 2 imaging substudies |
| Cardiovascular & Renal |
Under investigation in outcome trials; early data suggest blood pressure and lipid improvements beyond weight loss alone |
| NASH / MASLD |
Triple agonism may address multiple pathogenic drivers simultaneously: steatosis, inflammation, and fibrogenesis |
| Combination Potential |
Investigated with amylin analogs (e.g., cagrilintide) for additive metabolic effects |
Quality Specifications
| Parameter |
Specification |
Method |
| Purity (HPLC) |
≥99.0% |
RP-HPLC, 214 nm |
| Mass Identity |
MW ±1.0 Da |
ESI-MS |
| Water Content |
≤5.0% |
Karl Fischer titration |
| Peptide Content |
≥80.0% |
Amino acid analysis |
| Counterion |
Acetate (≤1.0% TFA) |
Ion chromatography |
| Endotoxin |
≤1.0 EU/mg |
LAL kinetic chromogenic |
| Residual Solvents |
≤ ICH Q3C limits |
Headspace GC |
| pH (1 mg/mL) |
4.5–7.0 |
Potentiometric |
Available Configurations
| Format |
Size |
Vials per Kit |
| Standard Research Kit |
5 mg × 10 vials |
10 |
| Extended Research Kit |
10 mg × 10 vials |
10 |
| Custom Configuration |
Per project |
Per scope |
Storage & Stability
| Condition |
Requirement |
| Short-term Storage |
2–8°C, lyophilized |
| Long-term Storage |
−20°C to −80°C, desiccated |
| Reconstituted |
24 h at 2–8°C; −20°C for freezer aliquots |
| Shipping |
Cold chain recommended; ambient ≤7 days |
Documentation
- COA per batch: chromatographic purity, MS identity, quantitative analysis
- MSDS provided with each shipment
Special Notes
- FOR LABORATORY RESEARCH USE ONLY.
- Retatrutide is an investigational compound. The synthesis complexity, while slightly less than tirzepatide due to more favorable solubility and purification characteristics, still requires advanced solid-phase peptide synthesis expertise and rigorous QC.
- Triple receptor agonism research should account for potential crosstalk between GIPR, GLP-1R, and GCGR signaling cascades when designing dose-response experiments.
- The GCGR component distinguishes retatrutide from dual agonists; researchers studying metabolic endpoints should consider including glucagon and FGF21 measurements in their protocols.
Key Research References
| Reference |
PMID |
Key Finding |
| Jastreboff AM et al. "Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial." N Engl J Med. 2023;389(6):514–526. |
37366315 |
Phase 2 trial: retatrutide produced up to 24.2% body weight reduction at 48 weeks; dose-dependent improvements in liver fat, lipids, and glycemic control |
| Coskun T et al. "LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept." Mol Metab. 2018;18:3–14. |
30473097 |
While primarily describing tirzepatide, this foundational paper also characterizes the GIP/GLP-1/GCGR triple agonism framework that enabled retatrutide's design; details C20 fatty acid linker and balanced receptor activity engineering |
Stability & Storage
| Condition |
Degradation Profile |
| Lyophilized Storage |
Standard GLP-1 receptor agonist family stability profile; no special handling beyond desiccated, temperature-controlled storage. 24 months at 2–8°C, 36 months at −20°C |
| Neutral pH (4.5–7.0) |
Stable; recommended pH range for reconstitution and working solutions |
| Acidic pH (<4.0) |
May promote aggregation of the C20 fatty diacid linker; avoid acidic buffers |
| Alkaline pH (>8.0) |
Risk of deamidation and C20 linker hydrolysis over extended incubation |
| Temperature Stress |
C20 eicosanedioic acid linker is hydrophobic; precipitation possible with temperature fluctuations. Gentle agitation recommended during reconstitution |
| Reconstituted Solution |
24 h at 2–8°C; aliquot and freeze at −20°C for ≤30 days |
Frequently Asked Questions
Q: What purity specifications apply to retatrutide?
≥99.0% by HPLC at 214 nm with ESI-MS mass identity confirmation (±1.0 Da). Comprehensive QC includes peptide content (≥80.0%), water content (≤5.0%), counterion analysis (acetate form, ≤1.0% TFA), and endotoxin testing (≤1.0 EU/mg). The intact C20 fatty diacid conjugate and full 39-aa sequence are confirmed in every batch-specific COA.
Q: How should retatrutide be stored after reconstitution?
Reconstituted retatrutide is stable for 24 hours at 2–8°C. For longer storage, aliquot into single-use portions and freeze at −20°C (stable ≤30 days). May require pH adjustment for complete dissolution. The C20 fatty acid linker is hydrophobic — gentle agitation, not vortexing, during reconstitution. Avoid repeated freeze-thaw cycles. Standard GLP-1 receptor agonist family storage conditions apply.
Source & Purchase
For researchers requiring RETATRUTIDE with full analytical documentation including HPLC and LC-MS traces, visit the PeptideSourceHub product page for bulk pricing and specifications.
Purchase RETATRUTIDE with COA →
| Product |
Link |
| Tirzepatide (Dual GIP/GLP-1) |
tirzepatide.md — First-in-class dual GIPR/GLP-1R agonist |
| Semaglutide (GLP-1 RA) |
semaglutide.md — Selective GLP-1 receptor agonist with C18 linker |
| Cagrilintide (Amylin Analog) |
cagrilintide.md — Long-acting amylin receptor agonist |
| AOD-9604 (hGH Fragment) |
aod-9604.md — Lipolytic hGH fragment 177-191 |