New perspective on type 2 diabetes and obesity treatment: study and development of new natural/synthetic inhibitors of tyrosine phosphatase 1B (PTP1B).

Type 2 diabetes mellitus (T2DM) is a complex disease characterized by impaired glucose homeostasis and serious long-term complications. First line therapeutic options for T2DM treatment are monodrug therapies, often replaced by multidrugs therapies to ensure that not responding patients maintain target levels of glycaemia. The use of multitarget drugs instead of mono- or multi-drugs therapies has been emerging as a main strategy to treat multifactorial diseases, including T2DM. Therefore, modern drug discovery in its early stages aims to identify potential modulators for multiple targets and exploration of the chemical space of natural products represents a powerful tool. For such purpose, we analyzed several natural/synthetic compounds which showed potent inhibition activity in vitro on PTP1B, the main negative regulator of insulin receptor and, for some of them, on aldose reductase (AR, target for treatment of T2D-related pathologies). These compounds are: the Epigallocatechin gallate (EGCG) obtained from tea extracts; Phosphoeleganin, a marine-derived phosphorylated polyketide; Gossypetin, which is the most potent inhibitor described so far within flavonoid class; Avarone, a sesquiterpene quinone obtained from the sponge Dysidea avara, and CA4-CA8, novel multi-target drugs specifically designed to target both PTP1B and AR. We analyzed their mechanisms of action, the kinetic behaviour coupled with in silico docking simulations and their effects on insulin-signalling pathway. We found that they acted as interesting antidiabetic agents by inhibiting PTP1B and enhancing glucose uptake in muscle cells even without the presence of insulin and, some of them also inhibited strongly the AR suggesting their usage as scaffold for multi-target drug development in order to deal with type 2 diabetes by acting on several targets involved at once.