In a study published in Scientific Reports, researchers engineer long-lasting GLP-1 receptor agonists by fusing GLP-1 with an HSA-binding protein. These chimeric molecules show promise for the treatment of type 2 diabetes due to their stability, functionality, and high affinity for the GLP-1 receptor and human serum albumin.
By Dr. Sushama R. Chaphalkar, PhD.Oct 22 2023Reviewed by Benedette Cuffari, M.Sc. In a study published in Scientific Reports, researchers engineer and computationally analyze three chimeric agonists of the glucagon-like peptide-1 receptor by fusing native and mutant GLP-1 with designed ankyrin repeat protein . This molecule binds human serum albumin .
GLP-1 and its analogs have shown promising results intreatingf T2DM in recent years; however, their therapeutic applicability is limited due to their short physiological half-lifeof lesss than two minutes. Therefore, there is a need to develop long-acting GLP-1 receptor agonists that resist proteolytic degradation and renal clearance.
The native GLP-1 and mGLP-1 molecules were each genetically fused to the N-terminus of DARPin using a rigid, helical linker to create three fusion proteins, including nGLP-1-DARPin, mGLP-1-DARPin-1, and mGLP-1-DARPin-2. The rigid linker helped maintain the distance between the domains of the protein, thereby enabling the preservation of their individual biological functions. The fusion proteins were made of 168 amino acids encoded by 504 nucleotides.
The dynamic behavior of the three fusion proteins was studied using molecular dynamics simulations for 500 nanoseconds using the GROMACS tool. To understand the affinity of proteins to HSA and GLP-1’s extracellular domain, protein-protein docking simulations were performed using the ClusPro 2.0 server. The HSA-estimated binding affinities of the proteins were used as indicators of their prolonged half-life and slower renal clearance.
The proteins were primarily composed of alpha helices and random coils, while beta-turns and extended strands were absent. Nuclear magnetic resonance -based structural analysis showed that the rigid linker used for fusion did not alter the structure or biological function of the fusion proteins as predicted by the 3D modeling tool. The results from the Ramachandran plot, ERRAT server, and ProSA server suggest that the quality of the predicted 3D models was good and comparable to native proteins.
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