Periodic Reporting for period 1 - RGD-Diabetes (Development of RGD-therapeutics for cardio-metabolic disease)
Periodo di rendicontazione: 2019-12-01 al 2021-11-30
RGD-Diabetes was a Proof-of-Concept project designed to advance fundamental scientific discoveries made during the ERC Starting Grant BP-CaRDiO. The intention was to develop putative new therapeutics diabetes, which now one in 11 adults worldwide and is a leading cause of heart attack, heart failure, stroke, blindness and kidney failure. In BP-CaRDiO we discovered that a circulating protein, insulin-like growth factor binding protein 1 (IGFBP1) had properties enabling it to protect against the development of type 2 diabetes and potentially to prevent cardiovascular disease. These properties are attributable to a part of the protein which contains a specific sequence called 'RGD'. We found that RGD-sequence binds to a receptor on muscle cells (called an integrin) to amplify the action of insulin and increase glucose uptake from the blood stream.
In the current project, RGD-Diabetes, we designed and tested small drug-like molecules with the intention that we could mimic the action of the RGD=sequence and increase the action of insulin on muscle cells. We used computer-based screening approaches to identify 30 compounds which we anticipated would bind to integrin receptors and mimic the actions of the RGD-sequence of IGFBP1. We confirmed that candidate compounds were able to augment insulin-signalling and glucose uptake in cultured skeletal muscle cells and from these successfully identified compounds for further development based on their solubility, stability and other properties. We therefore achieved our project aim, by achieving proof-of-concept that small-molecule mimetics of the RGD-motif of IGFBP1 can enhance insulin action and show promise for drug-development. We now intend to progress this research further towards the development of new therapeutics for diabetes. If successful, development of a new drug to prevent and treat diabetes which also has favourable cardiovascular effects could ultimately help millions of people worldwide.
In the current project, RGD-Diabetes, we designed and tested small drug-like molecules with the intention that we could mimic the action of the RGD=sequence and increase the action of insulin on muscle cells. We used computer-based screening approaches to identify 30 compounds which we anticipated would bind to integrin receptors and mimic the actions of the RGD-sequence of IGFBP1. We confirmed that candidate compounds were able to augment insulin-signalling and glucose uptake in cultured skeletal muscle cells and from these successfully identified compounds for further development based on their solubility, stability and other properties. We therefore achieved our project aim, by achieving proof-of-concept that small-molecule mimetics of the RGD-motif of IGFBP1 can enhance insulin action and show promise for drug-development. We now intend to progress this research further towards the development of new therapeutics for diabetes. If successful, development of a new drug to prevent and treat diabetes which also has favourable cardiovascular effects could ultimately help millions of people worldwide.