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

Abstract

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.

3-Benzylaminomethyl Lithocholic Acid Derivatives Exhibited Potent and Selective Uncompetitive Inhibitory Activity Against Protein Tyrosine Phosphatase 1B (PTP1B)

“…These interactions are noteworthy due to the reported presence of two alpha helices, residues 320–327 (α8’) and 360–377 (α9’) in the C-terminal domain. These helices have been reported to play a crucial role in PTP1B inhibition. , For 6e , the steroid backbone formed hydrophobic interactions with Trp 333, Val 334 , and Ile 346 . Interactions between the NH group and residues of α8’ helix (Lys 323 , Arg 325 ), and α9’ helix (Arg 371 ), an electropositive site of the unstructured region, were also observed, as well as an H-bond interaction between 3-OH group and Asn 321 (Figure S3).…”

“…Moreover, other serious pathologies have been associated with DM, such as an increased risk of developing cancer, liver disease, infection-related complications, and cognitive and affective disorders. 1,2 Some targets such as free fatty acid receptor 1 (FFAR1), αglucosidase, peroxisome proliferator-activated receptor-γ (PPARγ), dipeptidyl peptidase-4 (DPP4), sodium−glucose cotransporter 2 (SGLT2), aldose reductase (ALR), glycogen phosphorylase (GP), fructose-1,6-bisphosphatase (FBPase), glucagon receptor (GCGr), phosphoenolpyruvate carboxykinase (PEPCK), and protein tyrosine phosphatase 1B (PTP1B) have been identified to treat DM. 2,3 PTP1B is a negative insulin and leptin signaling pathway regulator, and a validated therapeutic target for DM and obesity.…”