Two separate studies have determined the structures of a drug class used to treat type 2 diabetes which could open up greater therapeutic options.
Two groups of US scientists have been analysing glucagon-like peptide-1 (GLP-1) receptor agonists, which work by stimulating the release of insulin and inhibiting glucagon, and how they bind to other peptides.
The nature of the interactions between GLP-1 agonists and other peptides “has been unknown and very difficult to model with any accuracy,” according to Patrick Sexton of Monash University, but this new research provides a much-needed breakthrough.
The findings from both studies show that peptide-receptor interactions could help researchers develop smaller-molecule drugs which will last longer in the body.
GLP-1 is rapidly broken down in the body; it is the peptides that mimic the activity of GLP-1 which have better stability and longevity which have been approved as type 2 diabetes drugs.
Moreover, the approved GLP-1 mimics are costly to produce, but the findings from these two studies could lead to the exploration of small peptides or GLP-1 mimicking molecules which are cheaper to make and, unlike existing medication, could be taken orally rather than via injection.
The results of the first study “provide a structural framework for understanding class B GPCR activation through hormone binding,” according to the researchers. Basically, they have worked out how GLP-1 receptors bind to full-length human GLP-1 peptides, which causes the signalling that helps regulate glucose metabolism and insulin release from the pancreas.
The second study used high resolution imaging to study these interactions in greater detail, which according to lead author Fiona H. Marshall, is “really important when you are doing structure-based design.”
Marshall and colleagues say that the complex nature of GLP-1 peptide-receptor interactions revealed in her findings “would be very difficult to mimic with a small-molecule drug, which would be the ideal if you wanted an oral therapy for diabetes.”
She added, though, that the information from her findings enabled her team to develop three smaller GLP-1 mimics which would be “easier to formulate as drugs” and “have the potential to be developed as oral therapies”.
Both studies have been published online in the journal Nature.

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