Diabetes mellitus (DM) is a common chronic disease in our Society. At each second one person dies due to DM worldwide. As DM is not curable, the therapeutic main goal is to control and treat it. The use of anti-diabetic drugs has significantly been increasing in Europe and Portugal is no exception. However, the average cost of these drugs more than duplicated in the last 10 years. Despite the therapeutics evolution, the currently available anti-diabetic drugs do not present the desired efficacy and are associated with serious adverse side effects. Thus, entirely new interventions to address the underlying etiopathogenesis of type 2 DM (DMT2) are required. Flavonoids have been considered a potential alternative strategy for the development of effective and safe anti-diabetic drugs. Our research group has an immense experience in the search and development of novel flavonoid scaffolds and defining their best structure-activity relationship, namely in the modulation of the inflammatory process. Interestingly, it is demonstrated that DM is associated to an increase in inflammatory markers (tumour necrosis factor, interleukin-6, etc.) and a decrease in anti-inflammatory mediators. Thus, targeting inflammation is important for the management of DM and related disorders. The noticeable inter-relation of these two pathologies, DM and inflammation, arouse our interest on the conjunction of the data that we already have on flavonoids? anti-inflammatory potential with the development of studies to promote the finding of new flavonoids structures targeting DMT2.
This project main goal is to uncover the best flavonoid scaffold to modulate enzymatic diabetic targets leading to an innovative treatment of DMT2. This will be achieved by an interdisciplinary working team, constituted by 3 research groups, with a very broad range of coordinated expertize, working together to accomplish the several stages of this project. In particular, this project will comprise 5 linked and interdependent stages: 1) virtual screening for the identification of new flavonoids acting on DMT2 targets and in silico optimization of the selected flavonoids, 2) in vitro testing of the first selected panel of flavonoids on DMT2 models, 3) synthesis and characterization of the flavonoids optimized in silico, 4) evaluation of their activity in the in vitro systems, and, finally, 5) in vivo evaluation of the most promising flavonoid(s) on animal models of DMT2. The most active flavonoids found will be patented, and considered as prototype for the design and development of potential anti-diabetic agents.
All in all, this project will provide a new light on the path to the treatment of the worldwide burden that is DMT2. It will evoke the improvement and application of techniques and processes that will clue the finding of new molecules to treat DMT2, leading to the creation of human, social and economic value, with high standards of excellence.