2025-06-05 タフツ大学
A tetra-agonist peptide (foreground helix) does the work of four separate hormones by binding to four different receptors (shown on the cell in red/blue, violet, blue, and green). “What drives us is the idea that we can design a single drug to treat obesity and simultaneously mitigate the risk of developing a long list of health problems plaguing society,” says Krishna Kumar. Image: Hassan @ScienceBrush
<関連情報>
- https://now.tufts.edu/2025/06/05/tufts-chemists-design-next-generation-weight-loss-drugs
- https://pubs.acs.org/doi/10.1021/jacs.5c04095
単分子テトラ受容体作動薬の分子設計 Molecular Design of Unimolecular Tetra-Receptor Agonists
Tristan C. Dinsmore,Jacob E. Cortigiano,Siyuan Xiang,Marina V. Spenciner,Alexandra R. Dobbins,Richard L. Zhao,Brett M. Waldman,Martin Beinborn,and Krishna Kumar
Journal of the American Chemical Society Published: June 3, 2025
DOI:https://doi.org/10.1021/jacs.5c04095
Abstract
Peptide hormone-receptor interactions serve as critical regulators of metabolic homeostasis, a paradigm exemplified by the clinical efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists. Building upon this framework, strategic design has yielded unimolecular dual and triple agonists targeting GLP-1R, glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon receptor (GcgR), leveraging the sequence homology within the cognate native ligands of the class B G protein-coupled receptor (GPCR) family. However, the integration of Y2 receptor (Y2R) agonism─engaged by peptide YY (PYY) and belonging to the structurally divergent class A GPCR family─has remained an unaddressed challenge due to the topological and sequence disparities between these receptor classes. Y2R activation plays a pivotal role in appetite suppression, potentiating the metabolic benefits conferred by GLP-1R, GIPR, and GcgR agonism. Here, we report first-in-class, unprecedented tetra-agonists with high potency at GLP-1R, GIPR, GcgR, and Y2R. The chimeric peptides overcome the intrinsic sequence constraints imposed by class A and class B GPCR divergence, demonstrating the feasibility of rationally designed agonism mediated by single agents across receptor families. Lipidation of this template is well tolerated enhancing the promise of therapeutic viability. Furthermore, we show that biased agonism at GLP-1R selectively boosts cyclic AMP (cAMP) signaling while minimizing β-arrestin recruitment, thereby decoupling receptor desensitization from metabolic efficacy. Additionally, we introduce a tunable framework to modulate β-arrestin engagement without compromising cAMP potency, providing insight into the fine-tuning of GPCR-mediated signaling for next-generation peptide therapeutics.
