AMYR
August 2026
Obesity remains a major global health challenge. It causes an increasing interest in therapies that engage complementary mechanisms of energy-balance regulation.
Amylin receptor agonism has emerged as a key focus in obesity drug discovery and development, with programs spanning early and late stages. Recent developments include:
Approaching a regulatory milestone: Novo Nordisk is awaiting an FDA decision on CagriSema - a cagrilintide–semaglutide combination for chronic weight management toward the end of 2026.
Intensifying competition: Zealand Pharma and Roche plan to advance the long-acting amylin analog (petrelintide) into Phase 3 trials, alongside Eli Lilly’s eloralintide (LY3841136), while Pfizer is developing the ultra-long-acting amylin analog (PF’3945).
Beyond peptides: Structure Therapeutics has advanced ACCG-2671, a potentially first-in-class oral small-molecule dual amylin and calcitonin receptor agonist, into Phase 1 development.
Despite rapid clinical development, is the molecular basis of amylin receptor activation fully understood? Recent cryo-EM structures provide new molecular insight into how a single amylin analog (cagrilintide) activates both the amylin receptor and the closely related calcitonin receptor, offering a structural framework for differentiating drug candidates and developing novel anti-obesity, dual-receptor agonists.
Key insights into a non-selective, dual amylin receptor activation
The amylin receptor (AMYR) is a modular class B GPCR system comprising the calcitonin receptor (CTR), which associates with one of three receptor activity-modifying proteins (RAMPs). Together, they form three amylin receptor subtypes: AMY₁R, AMY₂R, and AMY₃R, each with a distinct pharmacological profile. Activation of these receptors by amylin (an endogenous peptide hormone) or its analogs promotes earlier meal termination and reduces food intake, supporting body weight reduction over time.
Cagrilintide (Cagri) is a long-acting, lipidated amylin analog developed for chronic weight management and is the amylin component of the NovoNordisk’s CagriSema combination highlighted above. Unlike AMYRs, which consist of CTR associated with a RAMP, CTR can also function independently. Cagri activates both AMYRs and CTR alone, making it a non-selective dual amylin and calcitonin receptor agonist (DACRA).
The structural basis of its dual activity was unclear until recent insights came from a cryo-EM study of Cagri bound to Gs-coupled AMY₁R and CTR complexes. The key structural findings include:
Conserved “bypass” conformation: Cagri follows a similar overall binding trajectory in both AMY₁R and CTR. This “bypass” architecture is characteristic of amylin and amylin-like peptides bound to AMYRs, whereas ligands can adopt a distinct, CT-like binding mode in CTR alone. Unlike another DACRA, San45, which adopts different conformations in the two receptor systems, Cagri preserves the bypass mode in both.
In both receptor complexes, F23 in Cagri acts as a molecular anchor by inserting into a conserved hydrophobic pocket, stabilizing the conformation and therefore contributing to Cagri’s non-selective dual agonism.
Superposition of Cagrilintide bound to CTR (blue) and AMY₁R (orange) reveals a closely aligned peptide trajectory. F23 (green) is positioned at the TM1–TM2/ECL1 interface, helping stabilize the shared bypass conformation associated with dual receptor activation.
The image was produced with the 3decision® software.
2. Engineered dual receptor activation determinants: Beyond the F23-driven bypass architecture, several engineered features contribute to Cagri's activation mechanism in both receptor complexes:
An E14–R17 intramolecular salt bridge stabilizes the central α-helix, improving conformational rigidity relative to native amylin.
At the C-terminus, amidated P37 forms hydrophobic contacts with W79 ECD of both receptors, enabling strong CTR recognition without RAMP engagement and thereby reducing selectivity between CTR and AMYRs.
E14–R17 intramolecular salt bridge (green dashed line) in CTR-bound cagrilintide: E14 (red) and R17 (orange) stabilize the central α-helix of cagrilintide (blue); a corresponding interaction is observed in the AMY₁R-bound structure.
The image was produced with the 3decision® software.
3. Local receptor-specific contacts: Cagri engages distinct local interactions in CTR and AMY₁R. C2 in Cagri engages L298 in CTR but Y299 in AMY₁R. Alanine substitution of the respective receptor residues significantly reduced Cagri-mediated Gs activation, supporting the functional relevance of these distinct local environments. In AMY₁R, additional interactions between the flexible N-terminal lipid moiety and RAMP1 contribute to a slightly different peptide orientation.
Receptor-specific recognition of C2 Cagri: C2 Cagri is positioned near L298 in CTR (left in blue) but Y299 in AMY₁R (right in orange), as highlighted by the circles.
Images produced with the 3decision® software.
Conclusion
The novel structural findings explain how Cagri activates both AMY₁R and CTR despite their distinct receptor environments. As the amylin pipeline expands, this structural framework can support the rational design of next-generation anti-obesity therapeutics based on selective or dual receptor activation.
Reference:
Gu, Yi-Min et al. “Structural and mechanistic insights into dual activation of cagrilintide in amylin and calcitonin receptors.” Acta pharmacologica Sinica vol. 47,1 (2026): 162-172. doi:10.1038/s41401-025-01635-2
Structural exploration of the reference paper and images were produced using the 3decision® software.