Dual Targeting of PTP1B and Aldose Reductase with Marine Drug Phosphoeleganin: A Promising Strategy for Treatment of Type 2 Diabetes

Abstract

An in-depth study on the inhibitory mechanism on protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR) enzymes, including analysis of the insulin signalling pathway, of phosphoeleganin, a marine-derived phosphorylated polyketide, was achieved. Phosphoeleganin was demonstrated to inhibit both enzymes, acting respectively as a pure non-competitive inhibitor of PTP1B and a mixed-type inhibitor of AR. In addition, in silico docking analyses to evaluate the interaction mode of phosphoeleganin with both enzymes were performed. Interestingly, this study showed that phosphoeleganin is the first example of a dual inhibitor polyketide extracted from a marine invertebrate, and it could be used as a versatile scaffold structure for the synthesis of new designed multiple ligands.

Identifying Human PTP1B Enzyme Inhibitors from Marine Natural Products: Perspectives for Developing of Novel Insulin-Mimetic Drugs

“…The semisynthetic fragments 2 and 3, obtained from the oxidative cleavage of 1, were ineffective in inhibiting AR enzyme, too, ( Table S1 ). This finding can be interpreted in light of the previous results obtained from the in silico docking analysis of phosphoeleganin in the active site of AR [ 12 ]. The docking analysis indicated as relevant interactions for the inhibition of the catalytic activity of the enzyme those involving the more polar region of 1 (i.e., the region containing phosphate and OH groups).…”

“…In a previous study, we have demonstrated that phosphoeleganin ( 1 ), a phosphorylated poliketide isolated from the Mediterranean ascidian Sidnyum elegans , is able to inhibit both AR and PTP1B, acting as an insulin-sensitizing agent [ 12 ]. Therefore, in order to develop compound 1 as antidiabetic lead, we have carried out a sort of fragment-based approach by chemical manipulation of the natural metabolite and by synthesis of its simplified analogues.…”

“…We have recently discovered phosphoeleganin ( 1 ) ( Figure 1 ), a marine derived phosphorylated polyketide, as a dual inhibitor of the Protein Tyrosine Phosphatase 1B (PTP1B) and Aldose Reductase (AR) enzymes [ 10 , 11 , 12 ]. Both PTP1B and AR are considered as emerging targets involved in the onset and progression of chronic multifactorial diseases, such as type 2 Diabetes Mellitus (T2DM), obesity, cancer and, more generally, inflammatory-based diseases [ 13 , 14 ].…”

“…Phosphoeleganin has been demonstrated to inhibit both enzymes, acting, respectively, as a pure non-competitive inhibitor of PTP1B and a mixed-type inhibitor of AR. In addition, tests carried out using HepG2 cells confirmed that phosphoeleganin possesses an insulin-sensitizing activity [ 12 ]. To further explore and optimize the potential of this MNP as antidiabetic lead, as well as to overcome the supply issue, a common hurdle in the NPs based drug discovery, we have chemically manipulated the natural metabolite.…”

Insights into Cytotoxic Behavior of Lepadins and Structure Elucidation of the New Alkaloid Lepadin L from the Mediterranean Ascidian Clavelina lepadiformis

“…These data together with information by analysis of 2D NMR data allowed the sequential assignment of all the proto alkyl chain at C-5; indeed, 1 H-1 H spin system could be further extended to the s by following the chain of proton couplings from H-5 through to H-8′. The COSY In the frame of our research project aimed at the detailed chemical characterization of marine secondary metabolites from invertebrates [6,18,19], herein, we describe the results provided by the analysis of the metabolic content of the Mediterranean ascidian Clavelina lepadiformis. This analysis led to the isolation of the already known lepadins A (1) and B (2) [9,10] along with a new alkaloid belonging to the same family, named lepadin L (3, Figure 1).…”