Retatrutide (RETA) Peptide

Retatrutide is a first-in-class triple hormone receptor agonist that simultaneously activates GLP-1, GIP, and glucagon receptors. The GLP-1 and GIP receptor activation provides incretin-based appetite suppression and insulin secretion, while the unique glucagon receptor activation adds enhanced energy expenditure, fat oxidation, and hepatic lipid reduction — a mechanism absent from GLP-1 agonist peptide (GLP-1 only) and Tirzepatide (GLP-1/GIP only).

GLP-1 agonist peptide activates 1 receptor (GLP-1), Tirzepatide activates 2 receptors (GLP-1 + GIP), and Retatrutide activates 3 receptors (GLP-1 + GIP + glucagon). In Phase 2 trials, Retatrutide achieved -24.2% metabolic regulation research at 48 weeks — surpassing Tirzepatide (-20.9% at 72 weeks) and GLP-1 agonist peptide (-14.9% at 68 weeks). The additional glucagon receptor activation drives enhanced energy expenditure and hepatic fat reduction.

In the Phase 2 metabolic syndrome research trial (Jastreboff et al., NEJM 2023), the 12 mg Retatrutide group achieved: -24.2% mean body metabolic regulation research at 48 weeks, 100% of participants lost ≥5%, 93% lost ≥10%, 63% lost ≥20%, liver fat reduction of -82.4%, and improvements in blood pressure, triglycerides, and HbA1c.

Retatrutide has a molecular weight of 4,731.33 g/mol, molecular formula C₂₂₁H₃₄₂N₄₆O₆₈, and CAS number 2381089-83-2. It is a 39-amino acid peptide with three non-coded residues (Aib², Aib²⁰, αMeLeu¹³) and a C-20 fatty diacid albumin-binding moiety at Lys¹⁷.

Glucagon receptor (GCGR) activation increases hepatic energy expenditure via glycogenolysis and fatty acid oxidation, stimulates brown adipose tissue thermogenesis, and directly reduces liver fat. This third pathway explains why Retatrutide produces greater metabolic regulation research and liver fat reduction than dual GLP-1/GIP agonists. Phase 2 data showed -82.4% liver fat reduction, far exceeding results seen with GLP-1 agonist peptide or Tirzepatide.

Retatrutide is available in 10mg, 20mg, 30mg, 40mg, and 60mg lyophilized vials. All sizes are manufactured to ≥99% HPLC-verified purity with a Certificate of Analysis (COA) included. The fatty acid conjugation provides a ~6-day half-life enabling once-weekly research protocols.

Reconstitute with bacteriostatic water by slowly adding solvent along the inner vial wall — never directly onto the powder. Allow 5-10 minutes to dissolve without shaking. Retatrutide is a large (39-aa) fatty acid-conjugated peptide that is more sensitive to agitation than smaller peptides. The solution should be clear and colorless.

Lyophilized: -20°C for up to 24 months (long-term) or 2-8°C for up to 6 months. Reconstituted: 2-8°C, use within 21 days. Do not freeze reconstituted solution. Protect from light at all times. The fatty acid moiety provides some inherent stability but the peptide is still susceptible to oxidation and deamidation.

Retatrutide (retatrutide) exhibits a terminal half-life of approximately 6 days (~144 hours) following subcutaneous administration, as established in Phase 1 single-ascending-dose pharmacokinetic studies. This extended half-life is engineered through a C20 fatty diacid moiety conjugated to Lys17 via a γGlu-AEEA linker, which mediates reversible binding to serum albumin and protects the peptide from proteolytic clearance. The pharmacokinetic profile supports steady-state plasma concentrations with once-weekly subcutaneous dosing, achieving full equilibrium after approximately 4 weeks. This dosing interval is comparable to semaglutide and tirzepatide, both of which use similar albumin-binding fatty acid strategies.

The C20 dicarboxylic fatty acid attached to Lys17 (via a γ-glutamate and AEEA spacer) is the principal half-life extension element in Retatrutide. This lipid moiety enables high-affinity, reversible non-covalent binding to circulating serum albumin, which (1) shields the peptide backbone from dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidase cleavage, (2) reduces renal filtration by increasing apparent molecular size, and (3) creates a slow-release depot at the subcutaneous injection site. The Aib (α-aminoisobutyric acid) substitutions at positions 2 and 20 provide additional protease resistance. Together these modifications convert a peptide that would otherwise have a half-life of minutes into one suitable for weekly administration.

α-Methyl-leucine (αMeLeu) at position 13 of the Retatrutide sequence is a non-natural amino acid substitution that introduces steric bulk at the α-carbon. This modification confers resistance to enzymatic degradation by aminopeptidases and endopeptidases that would otherwise cleave at this position. αMeLeu also contributes to conformational stabilisation of the peptide's α-helical secondary structure, which is critical for high-affinity engagement with the GLP-1, GIP, and glucagon receptor extracellular domains. This unnatural residue, combined with the two Aib substitutions, exemplifies the rational peptide engineering strategy used to balance triple-receptor potency with metabolic stability.

As of 2026, Retatrutide (retatrutide / LY3437943) is not approved by the FDA, EMA, or any other regulatory agency. The compound is currently in Phase 3 clinical development under the TRIUMPH program for obesity, type 2 metabolic disorders, and metabolic dysfunction-associated steatohepatitis (MASH). AminoCore Research supplies retatrutide strictly as a research-grade peptide (≥99% HPLC purity) for in vitro and preclinical laboratory investigation only. It is not intended for human consumption, therapeutic use, diagnostic application, or any form of clinical administration. Researchers should consult their institutional biosafety and ethics committees before initiating any study.

In Phase 2 clinical research (Jastreboff et al., 2023), gastrointestinal effects were the most frequently reported adverse events associated with Retatrutide (retatrutide), consistent with the pharmacology of incretin receptor agonists. Nausea, diarrhea, and vomiting occurred in a dose-dependent manner, with most events graded as mild to moderate and primarily observed during the dose-escalation phase. The GLP-1 receptor component is believed to contribute to delayed gastric emptying and central appetite suppression, mechanisms shared with semaglutide and tirzepatide. Researchers studying tolerability profiles typically employ slow titration schedules to characterize these effects in preclinical models.

Retatrutide (retatrutide) is a 39-amino acid synthetic peptide with the sequence: YX-EGTFTSDYSIX-LDKKAQX-AFIEYLLEGGPSSGAPPPS, where X at position 2 represents α-methyl-2-aminoisobutyric acid (αMeAib), X at position 13 represents α-methyl-leucine (αMeLeu), and the lysine at position 20 is conjugated with a γ-glutamic acid spacer linked to a C20 fatty diacid (icosanedioic acid) moiety. This lipidation enables albumin binding for extended half-life. The peptide is C-terminally amidated. The structural design draws from the native glucagon backbone with strategic modifications enabling balanced triple agonism at GLP-1, GIP, and glucagon receptors.

Retatrutide (retatrutide) is used in in vitro and preclinical research to investigate triple incretin receptor pharmacology, metabolic regulation pathways, hepatic lipid metabolism (including MASLD/NASH models), glycemic homeostasis, energy expenditure mechanisms, and comparative pharmacology against dual agonists like tirzepatide and mono-agonists like semaglutide. The glucagon receptor component makes it particularly valuable for studying hepatic glucose output, lipolysis, and thermogenesis pathways that are not addressed by GLP-1/GIP-only compounds. Retatrutide is strictly for laboratory research use and is not intended for human or veterinary use.

The molecular formula of Retatrutide (retatrutide) is C221H343N45O68, with a molecular weight of approximately 4,731.45 g/mol. This formula reflects the 39-amino acid peptide backbone plus the γGlu-C20 diacid lipidation at the Lys20 position and C-terminal amidation. The CAS Registry Number is 2381089-83-2. These specifications have been verified against PubChem and published medicinal chemistry literature from Eli Lilly's discovery program (Coskun et al., 2022). Researchers should confirm certificate of analysis (COA) data for each lot to verify purity (≥99% by HPLC) and mass confirmation by ESI-MS.

Retatrutide is distinguished by its simultaneous agonism at three metabolic receptors: GLP-1, GIP, and glucagon. While semaglutide targets GLP-1 alone and tirzepatide engages GLP-1 and GIP, retatrutide adds glucagon receptor activation, which increases resting energy expenditure by 4-6% through hepatic thermogenic pathways. This third mechanism contributes to the compound producing approximately 24.2% body weight reduction in Phase 2 obesity trials — the largest magnitude reported for any Phase 2 pharmacological agent. The C20 fatty diacid modification enables albumin binding for a ~6-day half-life, supporting once-weekly research protocols.

Retatrutide demonstrates balanced but not equal potency across its three target receptors. In vitro binding studies show highest affinity for the GIP receptor, followed by glucagon receptor engagement roughly comparable to native glucagon, with GLP-1 receptor activation somewhat attenuated relative to semaglutide on a molar basis. This asymmetric profile was intentionally engineered — modest GLP-1 activity limits gastrointestinal adverse signaling while allowing GIP and glucagon pathways to drive energy expenditure and lipolysis. The αMeLeu (alpha-methyl leucine) substitution at position 2 confers DPP-IV resistance, and the C20 diacid at position 20 provides albumin binding for extended half-life.

Glucagon receptor agonism in the liver activates hepatic gluconeogenesis and, critically, increases fatty acid oxidation and mitochondrial thermogenesis. This produces a measurable increase in resting energy expenditure (4-6% in Phase 2 metabolic subanalyses) that is absent in GLP-1-only and GLP-1/GIP compounds. The glucagon component also enhances hepatic lipid mobilization, contributing to the 82-93% reduction in liver fat content observed in MASLD subanalyses of retatrutide trials. Concurrent GLP-1 activation suppresses glucagon's hyperglycemic potential by amplifying insulin secretion, allowing net glucose homeostasis to be maintained despite glucagon receptor engagement.

The C20 (icosanedioic acid) fatty diacid attached via a γGlu-2xOEG linker to Lys20 enables reversible non-covalent binding to serum albumin. This binding creates a circulating depot that dramatically extends the plasma half-life to approximately 6 days in humans, enabling once-weekly subcutaneous administration in research protocols. The C20 chain is longer than semaglutide's C18 diacid, providing tighter albumin association and more sustained exposure. Additionally, albumin binding shields the peptide backbone from proteolytic degradation and delays renal clearance. This lipidation strategy is a core structural feature enabling clinically practical dosing frequencies for peptide-based metabolic research compounds.