Protein tyrosine phosphatase 1B (PTP1B) function, structure, and inhibition strategies to develop antidiabetic drugs.

Tyrosine protein phosphatase non-receptor type 1 (PTP1B; also known as protein tyrosine phosphatase 1B) is a member of the protein tyrosine phosphatase (PTP) family and is a soluble enzyme that plays an essential role in different physiological processes, including the regulation of metabolism, specifically in insulin and leptin sensitivity. PTP1B is crucial in the pathogenesis of type 2 diabetes mellitus and obesity. These biological functions have made PTP1B validated as an antidiabetic and anti-obesity, and potentially anticancer, molecular target. Four main approaches aim to inhibit PTP1B: orthosteric, allosteric, bidentate inhibition, and PTPN1 gene silencing. Developing a potent and selective PTP1B inhibitor is still challenging due to the enzyme's ubiquitous expression, subcellular location, and structural properties. This article reviews the main advances in the study of PTP1B since it was first isolated in 1988, as well as recent contextual information related to the PTP family to which this protein belongs. Furthermore, we offer an overview of the role of PTP1B in diabetes and obesity, and the challenges to developing selective, effective, potent, bioavailable, and cell-permeable compounds that can inhibit the enzyme.

The importance of including the C-terminal domain of PTP1B1-400 to identify potential antidiabetic inhibitors.

In the present work, we studied the inhibitory and kinetic implications of classical PTP1B inhibitors (chlorogenic acid, ursolic acid, suramin) using three enzyme constructs (hPTP1B1-285, hPTP1B1-321, and hPTP1B1-400). The results indicate that the unstructured region of PTP1B (300-400 amino acids) is very important both to obtain optimal inhibitory results and propose classical inhibition mechanisms (competitive or non-competitive) through kinetic studies. The IC50 calculated for ursolic acid and suramin using hPTP1B1-400 are around four and three times lower to the short form of the enzyme, the complete form of PTP1B, the one found in the cytosol (in vivo). On the other hand, we highlight the studies of enzymatic kinetics using the hPTP1B1-400 to know the type of enzymatic inhibition and to be able to direct docking studies, where the unstructured region of the enzyme can be one more option for binding compounds with inhibitory activity.