Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by persistent high blood sugar levels and disruptions in carbohydrate, lipid, and protein metabolism due to a relative deficiency of insulin. In 2017, approximately 415 million adults worldwide were affected by T2DM, and this number is projected to increase to 629 million by 2045.
Despite the availability of various treatments for T2DM, including dietary changes, exercise, anti-diabetic medications, and insulin injections, managing blood glucose levels often proves challenging due to treatment inefficacy and patient non-compliance.Â
In recent years, there has been growing interest in the use of glucagon-like peptide-1 (GLP-1) and its analogs as promising medications for managing T2DM. GLP-1 is a 30-residue hormone secreted by the gut, primarily by L-cells in the distal ileum, in response to nutrient ingestion. This hormone plays a crucial role in regulating blood glucose levels through several mechanisms.
These include stimulating the insulin secretion process, suppressing the release of glucagon from the pancreas, enhancing feelings of satiety, slowing down stomach emptying, and reducing overall energy intake. To better understand the potential of engineered fusion proteins for T2DM treatment, researchers conducted three molecular dynamic simulations, each lasting 500 nanoseconds.
These simulations aimed to bridge the gap between theoretical concepts and experimental applications. Using computer-generated models, the team explored the stability of complex molecules and the likelihood of strong interactions between these molecules. Their selection criterion for the best-docked complex was the docking energy score, with lower scores indicating a higher binding affinity between the two proteins.Â
The results of these simulations demonstrated that all engineered fusion proteins had relatively high docking scores, indicating their potential for strong binding. Notably, when it came to binding affinity, the engineered fusion proteins displayed greater quantities for human serum albumin (HSA) compared to the GLP-1 receptor. This suggests that these fusion proteins have a higher potential for binding to HSA.Â
The primary goal of this research was to design and computationally analyze fusion proteins with high specificity and affinity for HSA and a protease-resistant GLP-1 peptide. The objective was to create potent GLP-1 agonists with extended plasma half-lives, addressing the issue of the rapid enzymatic degradation and short half-life of GLP-1, which is approximately 2 minutes.Â
Two specific fusion proteins were identified: mGLP1-DARPin-1, which demonstrated resistance to DPP-IV cleavage, making it suitable for use as a long-lasting injectable form of GLP-1, and mGLP1-DARPin-2, which exhibited resistance to both DPP-IV and trypsin cleavage, making it a candidate for oral delivery of GLP-1 encapsulated in plant cells. The in silico results of this study indicated that these engineered fusion proteins could effectively identify and bind to their target proteins, GLP-1R and HSA.
This methodology streamlines the initial analysis of engineered chimeric constructs before embarking on laboratory experiments with recombinant fusion proteins. It’s worth noting that the software and servers used in this process are freely available, making it a cost-effective and efficient approach, particularly for individuals new to this field.Â
This study showcases the potential of fusing peptide therapeutics with albumin-binding DARPins to enhance the effectiveness of short-circulating biologics, provided that the engineering is done correctly. While the computational analysis has identified three potential candidates as long-acting GLP-1 agonists, the next step involves establishing an experimental process, which is the ongoing focus of this research.Â
Journal Reference Â
Ehsasatvatan, M., Baghban Kohnehrouz, B. Designing and computational analyzing of chimeric long-lasting GLP-1 receptor agonists for type 2 diabetes. Sci Rep 13, 17778 (2023). https://doi.org/10.1038/s41598-023-45185-1. Â
