Eloralintide: Amylin Receptor Selectivity, Structure and Chemistry

Eloralintide is a lipidated amylin analogue developed under the code LY3841136 and assigned CAS number 2883634-40-8. The 2025 discovery report describes a 37-amino-acid chain containing three non-coded residues at positions 11, 15 and 22, a methylene thioacetal bridge in place of the native disulfide, and C-terminal amidation.

Acylation is the second defining feature. A saturated linear 20-carbon diacid is attached through a linker of two gamma-glutamate units to the lysine at position 26. Briere and colleagues state the purpose plainly: albumin association as a half-life extension mechanism, chosen to support a once-weekly interval rather than to add receptor contacts. The peptide is made by solid-phase synthesis and was studied in a pH 8 buffer, which the same paper contrasts with the pH 4 buffer used for cagrilintide.

Native human amylin sets the baseline the analogue departs from. The hormone is 37 residues long, closes an N-terminal ring through a disulfide between the cysteines at positions 2 and 7, and terminates in an amide. Eloralintide keeps that ring topology and the amide while changing the bond chemistry that closes the ring, and adds substitutions at three interior positions along with the lysine-26 conjugate.

Naming matters for retrieval. Three designations appear in indexed sources: eloralintide, the development code LY3841136, and the registry synonym AT53786. Searching the generic name alone misses records filed under the code.

Eloralintide acts on the calcitonin receptor family, a group of four related G protein-coupled receptors. The three amylin receptors arise from pairing of a single gene product, the calcitonin receptor, with an accessory subunit: RAMP1 gives AMY1R, RAMP2 gives AMY2R and RAMP3 gives AMY3R. The calcitonin receptor alone forms the fourth member.

In UMUC3 cells stably expressing the human receptors, cAMP accumulation gave a half-maximal effective concentration of 23.9 picomolar at AMY1R, against 291.0 picomolar at the calcitonin receptor and 253.8 picomolar at AMY3R. That is roughly 12-fold preference over the calcitonin receptor and 11-fold over AMY3R. Radioligand binding ran in the same direction but with a narrower margin: inhibition constants of 478.1 picomolar at AMY1R, 3896.1 picomolar at the calcitonin receptor and 3608.9 picomolar at AMY3R, about 8-fold either way.

Rat receptors gave a different pattern, which matters for anyone reading rodent work. Potencies were 5.4 picomolar at rAMY1R, 13.8 picomolar at rAMY3R and 243.2 picomolar at the rat calcitonin receptor, so both amylin subtypes were engaged far more readily than the calcitonin receptor: 45-fold and 18-fold respectively on activation, and 109-fold and 33-fold on binding affinity. Species is therefore a variable in the selectivity claim, not a constant.

Two assay conditions qualify these figures. Peptides were solubilized in DMSO, and comparisons ran without albumin so the acylated analogue could be set directly against unmodified natural peptides. Adding 1 percent human serum albumin lowered potency at all three human receptors, as expected for an albumin-binding conjugate, while the AMY1R preference over the calcitonin receptor persisted. Maximal response exceeded 80 percent at every receptor tested, so the molecule behaved as a full agonist throughout.

Eloralintide replaces the amylin disulfide with a methylene thioacetal, a bridge built by inserting a single carbon between the two sulfur atoms to give an S-CH2-S linkage. Zhou and colleagues reviewed the strategy in 2025 and named this molecule as one of its clinical-stage applications, alongside modified oxytocin and insulin analogues built on the same logic.

Geometrically the substitution is close to isosteric but not identical. The review reports a sulfur-to-sulfur separation of about 2.9 angstroms in the thioacetal against roughly 2.0 angstroms in a native disulfide, with small accompanying shifts in bond angle and local conformational preference. The practical consequence described is marginally increased rigidity in the macrocycle, which can be read either as a stability gain or as a constraint on how the ring presents itself to a receptor.

Redox behavior is where the two bridges genuinely diverge. A disulfide is reducible; a thioacetal is not. The review describes complete resistance to reduction in glutathione-rich conditions for a thioacetal oxytocin analogue, together with resistance to oxidative degradation and an approximately 5-fold serum stability improvement at physiological pH. An insulin analogue built the same way showed greater resistance to fibril formation and improved thermal and serum stability.

The aggregation problem this addresses is specific to the amylin scaffold. Islet amyloid polypeptide, the parent hormone, converts from a largely disordered monomer into ordered cross-beta-sheet assemblies, and Bousch and colleagues reviewed those conversion mechanisms in 2026 as the design constraint on non-aggregating analogues. Each long-acting analogue in this class answers it differently: helix-stabilizing substitutions in cagrilintide, chemical-stability optimization near neutral pH in petrelintide, an irreducible bridge here.

Eloralintide has no published experimental structure bound to any receptor, so the structural basis of its selectivity must be read from work on the receptor family and on related analogues. That literature is unusually good, and it converges on one region of the peptide: the midregion, residues roughly 19 through 25, which structural papers call the bypass motif.

Cao and colleagues addressed selectivity directly in Nature Chemical Biology. Working from cryo-EM structures and dynamics, they showed that targeted lipid modification within residues 19 to 22 tunes whether a peptide favors amylin receptors or the calcitonin receptor, and built two exemplars to prove it: San385, amylin-receptor selective, and San45, active at both classes. San45 carries its lipid at position 21, anchoring at the edge of the receptor helical bundle and opening an alternative binding mode at the calcitonin receptor alongside the bypass mode used at AMY3R. Lipid placement is therefore a selectivity determinant, not a purely pharmacokinetic choice.

A companion 2024 study resolved AMY1R with CGRP and the Gs protein, and compared it against the same receptor bound to rat amylin. Backbones matched closely at the receptor and at both peptide termini while the midregions organized differently, with divergent conformations in extracellular loop 3 and intracellular loops 2 and 3. Conserved C-terminal CGRP contacts were also traced, explaining why non-peptide CGRP receptor antagonists cross-react at AMY1R, which is worth knowing when interpreting any AMY1R assay.

Fairweather and colleagues supplied the ligand-free counterpart in 2026 using hydrogen-deuterium exchange mass spectrometry. Each accessory subunit altered calcitonin receptor flexibility in its own way across the extracellular domain, the transmembrane helices and the intracellular face that engages G protein. Read alongside the agonist-bound structures, that gives a physical account of why one receptor gene presents three distinguishable pharmacologies, the property this molecule was engineered to exploit.

Eloralintide behaves in circulation the way its acylation predicts. The 2025 discovery report gives geometric mean terminal half-life values of 310 to 366 hours in the first-in-human single-ascending study, equivalent to 12.9 to 15.3 days, with median time to peak concentration between 72.0 and 132.2 hours. Both figures are consistent with albumin-mediated retention rather than intrinsic peptide stability alone.

Exposure scaled predictably. Across the 0.4 to 12 mg range examined, area under the concentration-time curve extrapolated to infinity increased in proportion to the milligram amount, with a normalized geometric mean ratio of 0.975 and a 90 percent confidence interval of 0.803 to 1.18. Peak concentration rose less than proportionally, ratio 0.792 with an interval of 0.657 to 0.956. Between-participant variability was modest for a peptide: geometric mean coefficients of variation of 14 to 28 percent on exposure and 19 to 34 percent on peak concentration. The two lowest amounts examined, 0.04 and 0.12 mg, could not be characterized because sampling did not extend past two half-lives.

Bhattachar and colleagues reported the 12-week multiple-ascending study in 2026 across 100 participants, mean age 44 years, 29 percent female, mean body mass index 32.6 kilograms per square metre. Pharmacokinetics were again proportional to the milligram amount given at a once-weekly interval. Both studies quantified plasma by validated liquid chromatography-tandem mass spectrometry, the published analytical method of record for this molecule.

Preclinical comparisons appear qualitatively rather than as tables in the main text. In rats and in cynomolgus monkeys, the molecule showed higher exposure, longer half-life and flatter concentration-versus-time curves than cagrilintide, with the monkey work using a single 20 nmol/kg amount. Numerical preclinical parameters sit in supplementary tables rather than the body text.

Eloralintide carries a distinct set of registry identifiers that separate it from every other amylin analogue. PubChem CID 175663130 gives a molecular formula of C201H319N49O65S2, a molecular weight of 4526 grams per mole, an exact mass of 4525.2671 daltons and a monoisotopic mass of 4523.2604 daltons, with the InChIKey RLBIFQNAUXZCQB-UHFFFAOYSA-N.

Mass alone distinguishes it from its nearest structural relative. Cagrilintide is recorded at 4409 grams per mole with formula C194H312N54O59S2, so the two differ by roughly 117 mass units and by a large margin in nitrogen count, 49 against 54. Any mass-spectrometric identity check should resolve them without ambiguity, and the two sulfur atoms present in each formula reflect the two cysteine-derived positions rather than a shared bridge chemistry.

Computed descriptors are consistent with a large, highly polar lipopeptide: XLogP of -12.2, topological polar surface area of 1890 square angstroms, 60 hydrogen-bond donors, 70 acceptors, 141 rotatable bonds, 317 heavy atoms, a computed complexity of 11000 and a net formal charge of zero. These are calculated values from the PubChem record, not laboratory measurements, and should be cited as such.

One gap deserves stating rather than filling. The full residue-by-residue sequence has not been disclosed in the peer-reviewed record. The discovery paper identifies positions 11, 15 and 22 as non-coded without naming the residues, and describes the conjugate at position 26. Anyone requiring the complete sequence will need the patent literature, and any sequence circulating without a primary citation should be treated as unverified.

Eloralintide has very little published handling data, and the honest position is to say so. No peer-reviewed storage specification, solubility figure or solution-stability dataset for this specific molecule appears in the indexed literature as of August 2026. What exists are three facts from the discovery paper and one inference from the bridge chemistry.

The first is formulation pH. Material used in the reported studies sat in a pH 8 buffer, contrasted in the same paper with the pH 4 buffer used for cagrilintide. Buffer pH is not incidental for amylin analogues: the parent hormone's aggregation behavior is pH-sensitive, and formulation pH is a property medicinal-chemistry campaigns in this class actively optimize.

The second is the analytical method. Preclinical and clinical work both quantified the peptide in plasma by validated liquid chromatography-tandem mass spectrometry. No lower limit of quantification appears in the discovery paper's main text and no independent method paper exists for this analyte, so a laboratory needing a validated assay is building one rather than adopting one.

The third is in vitro solubilization: peptides in the reported receptor assays were dissolved in DMSO, and comparisons against natural peptides ran deliberately without albumin, because albumin binding suppresses apparent potency for acylated analogues. Reproducing those numbers requires matching that condition or expecting systematically weaker values.

The inference concerns reducing conditions. Because the ring closes through a methylene thioacetal rather than a disulfide, reducing agents that would open a conventional amylin ring should leave this bridge intact, and the chemistry review reports complete resistance to reduction for a thioacetal analogue built on the same principle. That has not been measured on this molecule, so it is a prediction from bridge chemistry rather than a published result.