Cagrilintide

Research Studies

(for educational purposes only)

Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors

Authors: Jianjun Cao, Matthew J. Belousoff, Rachel M. Johnson, Peter Keov, Zamara Mariam, Giuseppe Deganutti, George Christopoulos, Caroline A. Hick, Steffen Reedtz-Runge, Tine Glendorf, Borja Ballarín-González, Kirsten Raun, Charles Bayly-Jones, Denise Wootten & Patrick M. Sexton

Scientific Summary

This study utilized cryogenic electron microscopy (cryo-EM) to elucidate the structural basis of cagrilintide’s interaction with amylin receptors (AMY1R, AMY2R, AMY3R) and the calcitonin receptor (CTR). The high-resolution structures revealed that cagrilintide adopts an amylin-like binding mode, characterized by a ‘bypass’ motif. However, specific amino acid substitutions and the N-terminal lipidation in cagrilintide induce distinct conformational dynamics in the receptor complexes compared to native amylin or other analogues. These unique structural features, particularly the way it engages with the receptors, are proposed to contribute to its potent and long-acting clinical efficacy as a dual agonist for weight management.

Plain English Summary

Scientists used powerful microscopes to take detailed pictures of how the drug cagrilintide works at a molecular level. They found that it attaches to special sensors on cells, called receptors, in a way that is similar to a natural hormone called amylin, which helps control appetite. However, cagrilintide has some unique features that make it interact with these receptors in a special way, causing a stronger and longer-lasting effect. This helps explain why cagrilintide is so effective at helping people lose weight.

Development of Cagrilintide, a Long-Acting Amylin Analogue

Authors: Thomas Kruse, Jakob Lerche Hansen, Kirsten Dahl, Lauge Schäffer, Ulrich Sensfuss, Christian Poulsen, Morten Schlein, Ann Maria Kruse Hansen, Claus Bekker Jeppesen, Charlotta Dornonville de la Cour, Trine Ryberg Clausen, Eva Johansson, Simone Fulle, Rikke Bjerring Skyggebjerg, Kirsten Raun

Scientific Summary

This paper details the medicinal chemistry efforts that led to the design and synthesis of cagrilintide, a long-acting amylin analogue for the treatment of obesity. Through a series of structure-activity relationship (SAR) studies, the authors optimized the peptide sequence and introduced a C20 fatty diacid via a γ-glutamic acid linker to the N-terminus. In vitro functional assays, including luciferase and cAMP assays, were performed on cell lines expressing human and rat amylin and calcitonin receptors. These experiments confirmed that cagrilintide is a potent dual agonist, activating both receptor types, which is crucial for its therapeutic effect on reducing food intake and body weight, as demonstrated in preclinical rat models.

Plain English Summary

This research paper describes how scientists designed and created the drug cagrilintide. They started with a natural hormone called amylin and made specific changes to its structure to make it more effective and last longer in the body. One key change was adding a fatty acid molecule, which helps the drug to be released slowly. They then tested the new drug in the lab on cells that have the same sensors as our own body. The results showed that cagrilintide is very good at activating these sensors, which in turn helps to control appetite and reduce body weight.

Does receptor balance matter? – Comparing the efficacies of the dual amylin and calcitonin receptor agonists cagrilintide and KBP-336 on metabolic parameters in preclinical models

Authors: A.T. Larsen, K.E. Mohamed, N. Sonne, E. Bredtoft, F. Andersen, M.A. Karsdal, K. Henriksen

Scientific Summary

This study conducted a head-to-head comparison of two dual amylin and calcitonin receptor agonists (DACRAs), cagrilintide and KBP-336, to investigate the importance of their receptor activation balance. Using in vitro cell-based assays, the researchers found that while both peptides activated the amylin and calcitonin receptors, KBP-336 was more potent and showed a bias towards the calcitonin receptor compared to cagrilintide. Cagrilintide’s potency on both receptors was found to be similar to their natural ligands, confirming its role as a balanced dual agonist. These in vitro findings highlight that even within the same class of drugs, subtle differences in how they interact with their target receptors can exist, which may translate to different overall effects in the body.

Plain English Summary

In this study, scientists compared two similar drugs, cagrilintide and KBP-336, to see if there were any important differences in how they work. Both drugs are designed to activate two different sensors in the body that help control metabolism. In lab experiments, they found that both drugs did their job, but KBP-336 was more powerful and leaned more towards activating one of the sensors over the other. Cagrilintide, on the other hand, was more balanced in how it activated both sensors. This research shows that even very similar drugs can have slight differences in their actions, which could be important for how they affect the body.