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Enabling structure-based design for metabolic disease
by Jeffrey Bouley  |  Email the author


LONDON—Heptares Therapeutics, a wholly-owned subsidiary of Sosei Group Corp., recently announced that its scientists have solved the high-resolution X-ray crystal structures of the GLP-1 (glucagon-like peptide 1) and glucagon receptors. An important achievement, given that both receptors are important players in the maintenance of blood glucose levels and both are seen as important targets for therapeutic in the metabolic disease realm, such as treatments for diabetes.
This is explained in the journal article “Extra-helical binding site of a glucagon receptor antagonist,” which appeared in Nature this month in more detail of course, but to break it down more succinctly, the work by Heptares scientists in solving the X-ray structure of the full length GLP-1 receptor bound to a peptide agonist represents the first time that a receptor of this class has been resolved in its active state conformation, according to the company. Having access to a high-resolution structure of the GLP-1 receptor in this conformation could be an important part of future work on the discovery and development of small-molecule oral drugs designed to treat or cure metabolic diseases.
The findings described by Heptares scientists focus on the identification of a novel binding site distinct from the glucagon-binding site. This “allosteric” binding site is located outside the transmembrane domain of the receptor, at the interface with the cell membrane, and is shown to inhibit the normal signaling function of the receptor when bound to small-molecule antagonist MK-0893.
Heptares is using the structural and physicochemical information derived from its research on the GLP-1 and glucagon receptors—and from other receptors in the same class, such as class B GPCRs [G protein-coupled receptors], including the previously solved CRF-1 receptor—to advance allosteric small-molecule GLP-1 antagonists toward the clinic as potential new treatments for the rare disease congenital hyperinsulinaemia.
The new structural information generated by Heptares from the research on these receptors adds to the growing information already being generated using its StaR platform on GPCRs, the most important family of receptors targeted by drug developers. This resource, including detailed X-ray structures from more than 12 GPCRs solved by Heptares scientists, is enabling the company to apply its structure-based design platform to develop therapeutics (small molecules and biologics) for these and structurally similar receptors that have strong links to disease.
“Heptares continues to demonstrate the power of its StaR technology to elucidate the structure of important GPCRs and apply this knowledge to its drug design programs and those of it partners,” said Fiona Marshall, chief scientific officer at Heptares. “Our pioneering research is greatly enhancing our ability to apply our structure-based approach to drug discovery across a wide range of GPCR targets with strong clinical validation, but which have proved difficult or impossible to access previously.”
Class B GPCRs represent a family of structurally similar receptors for peptide hormones such as GLP-1, glucagon, corticotropin-releasing factor, calcitonin and parathyroid peptide hormone. Class B GPCRs include many therapeutic targets for cardiovascular diseases, metabolic diseases, bone diseases and migraine, but despite strong clinical validation, structural information is limited, according to Heptares.
Code: E04271604



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