Targeting Protein Tyrosine Phosphatase Research Articles

Previously Published Phosphatase Probes Have Limited Utility Due To Their Unspecific Reactivity.

This study explores using activity-based protein profiling to target protein tyrosine phosphatases. With the discovery of allosteric SHP2 inhibitors, this enzyme family has resurfaced as interesting drug targets. Therefore, we envisioned that previously described direct electrophiles and quinone methide-based traps targeting phosphatases could be applied in competitive activity-based protein profiling assays. This study evaluates three direct electrophiles, specifically, a vinyl sulfonate, a vinyl sulfone, and an α-bromobenzylphosphonate as well as three quinone methide-based traps as activity-based probes. For all these moieties it was previously shown that they could selectively engage with phosphatases in assays with purified enzymes or overexpressed phosphatases in bacterial lysates. However, this study demonstrates that probes based on these moieties all suffer from unspecific labelling. Direct electrophiles were either unspecific or not activity-based, while quinone methide-based traps showed dependence on phosphatase activity but also resulted in unspecific labelling due to diffusion after activation. This phenomenon, termed 'bystander' labelling, occurred even with catalytically inactive SHP2 mutants. We concluded that alternative strategies or chemistries are needed to apply activity-based protein profiling in phosphatase research. Moreover, this study shows that quinone methide-based designs have limited potential in probe and inhibitor development strategies due to their intrinsic reactivity.

Tumor microenvironment responsive nano-herb and CRISPR delivery system for synergistic chemotherapy and immunotherapy

Chemoresistance remains a significant challenge for effective breast cancer treatment which leads to cancer recurrence. CRISPR-directed gene editing becomes a powerful tool to reduce chemoresistance by reprogramming the tumor microenvironment. Previous research has revealed that Chinese herbal extracts have significant potential to overcome tumor chemoresistance. However, the therapeutic efficacy is often limited due to their poor tumor targeting and in vivo durability. Here we have developed a tumor microenvironment responsive nanoplatform (H-MnO2(ISL + DOX)-PTPN2@HA, M(I + D)PH) for nano-herb and CRISPR codelivery to reduce chemoresistance. Synergistic tumor inhibitory effects were achieved by the treatment of isoliquiritigenin (ISL) with doxorubicin (DOX), which were enhanced by CRISPR-based gene editing to target protein tyrosine phosphatase non-receptor type 2 (PTPN2) to initiate long-term immunotherapy. Efficient PTPN2 depletion was observed after treatment with M(I + D)PH nanoparticles, which resulted in the recruitment of intratumoral infiltrating lymphocytes and an increase of proinflammatory cytokines in the tumor tissue. Overall, our nanoparticle platform provides a diverse technique for accomplishing synergistic chemotherapy and immunotherapy, which offers an effective treatment alternative for malignant neoplasms.Graphical

Identification of Potent Inhibitors Targeting Protein Tyrosine Phosphatase 1B

Identification of Potent Inhibitors Targeting Protein Tyrosine Phosphatase 1B

Promising natural products targeting protein tyrosine phosphatase SHP2 for cancer therapy.

The development of Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors is a hot spot in the research and development of antitumor drugs, which may induce immunomodulatory effects in the tumor microenvironment and participate in anti-tumor immune responses. To date, several SHP2 inhibitors have made remarkable progress and entered clinical trials for the treatment of patients with advanced solid tumors. Multiple compounds derived from natural products have been proved to influence tumor cell proliferation, apoptosis, migration and other cellular functions, modulate cell cycle and immune cell activation by regulating the function of SHP2 and its mutants. However, there is a paucity of information about their diversity, biochemistry, and therapeutic potential of targeting SHP2 in tumors. This review will provide the structure, classification, inhibitory activities, experimental models, and antitumor effects of the natural products. Notably, this review summarizes recent advance in the efficacy and pharmacological mechanism of natural products targeting SHP2 in inhibiting the various signaling pathways that regulate differentcancers and thus pave the way for further development of anticancer drugs targeting SHP2.

Melanoxetin: A Hydroxylated Flavonoid Attenuates Oxidative Stress and Modulates Insulin Resistance and Glycation Pathways in an Animal Model of Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (DM) continues to escalate, necessitating innovative therapeutic approaches that target distinct pathways and address DM complications. Flavonoids have been shown to possess several pharmacological activities that are important for DM. This study aimed to evaluate the in vivo effects of the flavonoid melanoxetin using Goto-Kakizaki rats. Over a period of 14 days, melanoxetin was administered subcutaneously to investigate its antioxidant, anti-inflammatory, and antidiabetic properties. The results show that melanoxetin reduced insulin resistance in adipose tissue by targeting protein tyrosine phosphatase 1B. Additionally, melanoxetin counteracted oxidative stress by reducing nitrotyrosine levels and modulating superoxide dismutase 1 and hemeoxygenase in adipose tissue and decreasing methylglyoxal-derived hydroimidazolone (MG-H1), a key advanced glycation end product (AGE) implicated in DM-related complications. Moreover, the glyoxalase 1 expression decreased in both the liver and the heart, correlating with reduced AGE levels, particularly MG-H1 in the heart. Melanoxetin also demonstrated anti-inflammatory effects by reducing serum prostaglandin E2 levels, and increasing the antioxidant status of the aorta wall through enhanced acetylcholine-dependent relaxation in the presence of ascorbic acid. These findings provide valuable insights into melanoxetin's therapeutic potential in targeting multiple pathways involved in type 2 DM, particularly in mitigating oxidative stress and glycation.

Targeting Protein Tyrosine Phosphatases to Improve Cancer Immunotherapies.

Advances in immunotherapy have brought significant therapeutic benefits to many cancer patients. Nonetheless, many cancer types are refractory to current immunotherapeutic approaches, meaning that further targets are required to increase the number of patients who benefit from these technologies. Protein tyrosine phosphatases (PTPs) have long been recognised to play a vital role in the regulation of cancer cell biology and the immune response. In this review, we summarize the evidence for both the pro-tumorigenic and tumour-suppressor function of non-receptor PTPs in cancer cells and discuss recent data showing that several of these enzymes act as intracellular immune checkpoints that suppress effective tumour immunity. We highlight new data showing that the deletion of inhibitory PTPs is a rational approach to improve the outcomes of adoptive T cell-based cancer immunotherapies and describe recent progress in the development of PTP inhibitors as anti-cancer drugs.

Revisiting New Classes of Chalcones from Antidiabetic Perspectives

Elevated blood sugar levels and a plethora of other, more diverse diseases, including changes to protein, carbohydrate, and lipid metabolism, are the only hallmarks of diabetes mellitus. Recent research has shown that mice lacking PTP1B had better glucose tolerance, less diet-induced obesity, and insulin sensitivity in general. In the therapy of serious diabetic problems, natural chalcones have recently been discovered, which have superior selectivity and do not affect pharmacokinetics. This is in response to the present demand for improved PTP-1B inhibitors. No appropriate formulation has been developed for the inhibitors based on natural products chalcones as they have not been tested clinically for toxicological characteristics. The review article has extensively covered various unknown natural chalcone compounds, such as kuwanon J, kuwanon R, kuwanon V, isoliquiritigenin, xanthoangelol, xanthoangelol D, xanthoangelol E, xanthoangelolF, xanthoangelol K, 4-hydroxyderricin, 5,4’-dihydroxy-6,7- furanbavachalcone, licochalcone A, licochalcone B, licochalcone C, licochalcone D, licochalcone E, echinatin, laxichalcone, broussochalcone, macdentichalcone, (2E)1, 1-(5,7-dihydroxy-2,2-dimethyl-2H-benzopyran-8-yl)}3-phenyl-2-propen-1-one, often known as 2E(abyssinone-VI-4-O-methyl ether, 1-(5,7-dihydroxy-2,2,6-trimethyl-2H-benzopyran-8-yl)-3-(4-methoxyphenyl)- 2-propen-1-one) show great promise as a diabetic medication because it can inhibit insulin degradation by targeting the therapeutic target protein tyrosine phosphatase 1B (PTP-1B). These chalcone-based PTP-1B inhibitors derived from natural products are not currently used in clinical trials and have not attracted much interest from contemporary medicine due to a lack of clinical investigation into their toxicological profiles necessary to create an appropriate formulation. These chalcone-based PTP-1B inhibitors may soon unlock new opportunities in diabetotherapeutics.

Targeting protein tyrosine phosphatases for CDK6-induced immunotherapy resistance

Elucidating the mechanisms of resistance to immunotherapy and developing strategies to improve its efficacy are challenging goals. Bioinformatics analysis demonstrates that high CDK6 expression in melanoma is associated with poor progression-free survival of patients receiving single-agent immunotherapy. Depletion of CDK6 or cyclin D3 (but not of CDK4, cyclin D1, or D2) in cells of the tumor microenvironment inhibits tumor growth. CDK6 depletion reshapes the tumor immune microenvironment, and the host anti-tumor effect depends on cyclin D3/CDK6-expressing CD8+ and CD4+ Tcells. This occurs by CDK6 phosphorylating and increasing the activities of PTP1B and Tcell protein tyrosine phosphatase (TCPTP), which, in turn, decreases tyrosine phosphorylation of CD3ζ, reducing the signal transduction for Tcell activation. Administration of a PTP1B and TCPTP inhibitor prove more efficacious than using a CDK6 degrader in enhancing Tcell-mediated immunotherapy. Targeting protein tyrosine phosphatases (PTPs) might be an effective strategy for cancer patients who resist immunotherapy treatment.

PTPN14 promotes gastric cancer progression by PI3KA/AKT/mTOR pathway

Gastric cancer is a high molecular heterogeneous disease with a poor prognosis. Although gastric cancer is a hot area of medical research, the mechanism of gastric cancer occurrence and development is still unclear. New strategies for treating gastric cancer need to be further explored. Protein tyrosine phosphatases play vital roles in cancer. A growing stream of studies shows that strategies or inhibitors targeting protein tyrosine phosphatases have been developed. PTPN14 belongs to the protein tyrosine phosphatase subfamily. As an inert phosphatase, PTPN14 has very poor activity and mainly functions as a binding protein through its FERM (four-point-one, ezrin, radixin, and moesin) domain or PPxY motif. The online database indicated that PTPN14 may be a poor prognostic factor for gastric cancer. However, the function and underlying mechanism of PTPN14 in gastric cancer remain unclear. We collected gastric cancer tissues and detected the expression of PTPN14. We found that PTPN14 was elevated in gastric cancer. Further correlation analysis indicated that PTPN14 was relevant with the T stage and cTNM (clinical tumor node metastasis classification) stage. The survival curve analysis showed that gastric cancer patients with higher PTPN14 expression had a shorter survival time. In addition, we illustrated that CEBP/β (CCAAT enhanced binding protein beta) could transcriptionally activate PTPN14 expression in gastric cancer. The highly expressed PTPN14 combined with NFkB (nuclear factor Kappa B) through its FERM domain and accelerated NFkB nucleus translocation. Then, NFkB promoted the transcription of PI3KA and initiated the PI3KA/AKT/mTOR pathway to promote gastric cancer cell proliferation, migration, and invasion. Finally, we established mice models to validate the function and the molecular mechanism of PTPN14 in gastric cancer. In summary, our results illustrated the function of PTPN14 in gastric cancer and demonstrated the potential mechanisms. Our findings provide a theoretical basis to better understand the occurrence and development of gastric cancer.

In Silico Analysis of PTP1B Inhibitors and TLC-MS Bioautography-Based Identification of Free Radical Scavenging and α-Amylase Inhibitory Compounds from Heartwood Extract of Pterocarpus marsupium.

Type 2 diabetes mellitus leads to metabolic impairment caused by insulin resistance and hyperglycemia, giving rise to chronic diabetic complications and poor disease prognosis. The heartwood of Pterocarpus marsupium has been used in Ayurveda for a long time, and we sought to find the actual mechanism(s) driving its antidiabetic potential. Methanol was used to prepare the extract using a Soxhlet extraction, and the identification of metabolites was performed by thin-layer chromatography (TLC) and ultraperformance-liquid chromatography and mass spectroscopy (UP-LCMS). The antioxidant potential of methanolic heartwood extract of Pterocarpus marsupium MHPM was determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and a reducing power assay. The α-amylase and α-glucosidase enzyme inhibitory potential of MHPM were investigated for their antidiabetic activity against acarbose. TLC-MS-bioautography was performed to identify the compounds responsible for possible antioxidant and antidiabetic activities. Moreover, targeting protein tyrosine phosphatase 1B (PTP1B), a key regulator of insulin resistance, by identified metabolites from MHPM through molecular docking and all-atom molecular dynamics (MD) simulations was also undertaken, suggesting its potential as an antidiabetic herb. The IC50 of free-radical scavenging activity of MHPM against DPPH was 156.342 ± 10.70 μg/mL. Further, the IC50 values of MHPM in α-amylase and α-glucosidase enzymatic inhibitions were 158.663 ± 10.986 μg/mL and 180.21 ± 11.35 μg/mL, respectively. TLC-MS-bioautography identified four free radical scavenging metabolites, and vanillic acid identified by MS analysis showed both free radical scavenging activity and α-amylase inhibitory activity. Among the identified metabolites from MHPM, epicatechin showed significant PTP1B docking interactions, and its MD simulations revealed that PTP1B forms a stable protein-ligand complex with epicatechin throughout the progression, which indicates that epicatechin may be used as a promising scaffold in the development of the antidiabetic drug after isolation from Pterocarpus marsupium. Overall, these findings imply that Pterocarpus marsupium is a source of valuable metabolites that are accountable for its antioxidant and antidiabetic properties.

Extracellular vesicles microRNA-592 of melanoma stem cells promotes metastasis through activation of MAPK/ERK signaling pathway by targeting PTPN7 in non-stemness melanoma cells

Melanoma, one of the most aggressive malignancies, its high mortality and low survival rates are associated with effective metastatic colonization. Melanoma metastasis hinges on the bidirectional cell-cell communication within the complex metastatic microenvironments (MME). Extracellular vesicles (EVs) are recognized as a new class of molecular mediator in MME programing. Published studies show that melanoma EVs can educate MME stromal cells to acquire the pro-metastatic phenotype to enhance metastatic colonization. Whether EVs can mediate the interactions between heterogenous cancer cells within the MME that alter the course of metastasis has not been investigated at the mechanistic level. In this study, melanoma parental cells (MPCs) and paired derivative cancer stem cell line melanoma stem cells (MSCs) that were derived from melanoma cell line M14 were used. We demonstrate that the EVs-mediated crosstalk between the MSCs and the MPCs is a novel mechanism for melanoma metastasis. We characterized miR-592, a relatively novel microRNA of prognostic potential, in mediation of such intercellular crosstalk. EVs can encapsulate and deliver miR-592 to target MPCs. Upon entering, miR-592 inhibits the expression of its gene target protein tyrosine phosphatase non-receptor type7 (PTPN7), a phosphatase targeting MAPKs. This leads to the relief of the inhibitory effect of PTPN7 on MAPK/ERK signaling and consequently the augmentation of metastatic colonization of MPCs. Thus, via the extracellular vesicle miR-592/PTPN7/MAPK axis, melanoma-CSCs can transfer their metastatic ability to the low-metastatic non-CSC melanoma cells.

Identification of Flavonoid C-Glycosides as Promising Antidiabetics Targeting Protein Tyrosine Phosphatase 1B.

Protein tyrosine phosphatase 1B (PTP1B), a negative regulator of the insulin signaling pathway, has gained attention as a validated druggable target in the management of type 2 diabetes mellitus (T2DM). The lack of clinically approved PTP1B inhibitors has continued to prompt research in plant-derived therapeutics possibly due to their relatively lesser toxicity profiles. Flavonoid C-glycosides are one of the plant-derived metabolites gaining increased relevance as antidiabetic agents, but their possible mechanism of action remains largely unknown. This study investigates the antidiabetic potential of flavonoid C-glycosides against PTP1B in silico and in vitro. Of the seven flavonoid C-glycosides docked against the enzyme, three compounds (apigenin, vitexin, and orientin) had the best affinity for the enzyme with a binding score of –7.3 kcal/mol each, relative to –7.4 kcal/mol for the reference standard, ursolic acid. A further probe (in terms of stability, flexibility, and compactness) of the complexes over a molecular dynamics time study of 100 ns for the three compounds suggested orientin as the most outstanding inhibitor of PTP1B owing to its overall -34.47 kcal/mol binding energy score compared to ursolic acid (-19.24 kcal/mol). This observation was in accordance with the in vitro evaluation result, where orientin had a half maximal inhibitory concentration (IC50) of 0.18 mg/ml relative to 0.13 mg/ml for the reference standard. The kinetics of inhibition of PTP1B by orientin was mixed-type with Vmax and Km values of 0.004 μM/s and 0.515 μM. Put together, the results suggest orientin as a potential PTP1B inhibitor and could therefore be further explored in the management T2DM as a promising therapeutic agent.

The Emerging Target Protein Tyrosine Phosphatase 1B (PTP1B) for Type 2 Diabetes Mellitus Management

Type 2 diabetes mellitus is one of the greatest health burdens of our society. Despite the extensive options of current drug treatments, novel therapies are under development to manage this chronic disorder and its subsequent complications. The inhibition of the enzyme protein tyrosine phosphatase 1B (PTP1B) is a promising therapeutic intervention in diabetes and obesity. However, finding selective PTP1B inhibitors remains a challenge. The pyrazole scaffold is considered of high pharmaceutical interest due to the high range of pharmacological activities. Nonetheless, the study of their effect against PTP1B activity have not yet been fully explored, opening a new field of research to find a new potential approach for type 2 diabetes mellitus management. This commentary presents and discusses PTP1B as an emerging target for type 2 diabetes mellitus management.

Targeting Protein Tyrosine Phosphatase 22 Does Not Enhance the Efficacy of Chimeric Antigen Receptor T Cells in Solid Tumors.

Adoptive cell therapy with chimeric antigen receptor (CAR) T cells has revolutionized the treatment of certain B cell malignancies but has been in ineffective against solid tumors. Recent studies have highlighted the potential of targeting negative regulators of T cell signaling to enhance the efficacy and extend the utility of CAR T cells to solid tumors. Autoimmunity-linked protein tyrosine phosphatase N22 (PTPN22) has been proposed as a target for cancer immunotherapy. Here, we have used CRISPR/Cas9 gene editing to generate PTPN22-deficient (Ptpn22Δ/Δ) mice (C57BL/6) and assessed the impact of PTPN22 deficiency on the cytotoxicity and efficacy of CAR T cells in vitro and in vivo. As reported previously, PTPN22 deficiency was accompanied by the promotion of effector T cell responses ex vivo and the repression of syngeneic tumor growth in vivo. However, PTPN22 deficiency did not enhance the cytotoxic activity of murine CAR T cells targeting the extracellular domain of the human oncoprotein HER2 in vitro. Moreover, PTPN22-deficient α-HER2 CAR T cells or ovalbumin-specific OT-I CD8+ T cells adoptively transferred into mice bearing HER2+ mammary tumors or ovalbumin-expressing mammary or colorectal tumors, respectively, were no more effective than their wild-type counterparts in suppressing tumor growth. The deletion of PTPN22 using CRISPR/Cas9 gene editing also did not affect the cytotoxic activity of human CAR T cells targeting the Lewis Y antigen that is expressed by many human solid tumors. Therefore, PTPN22 deficiency does not enhance the antitumor activity of CAR T cells in solid organ malignancies.

Targeting protein tyrosine phosphatase 1B in obesity-associated colon cancer: Possible role of sweet potato (Ipomoea batatas).

Protein tyrosine phosphatase 1B (PTP1B) has emerged as one of the links between obesity and colon cancer (CC). Anti-obesity and anti-CC attributes of sweet potato (Ipomoea batatas) reported sparsely. Here, we aimed to study the potential of PTP1B as a target in CC, particularly in obese population. Expression and genomic alteration frequency of PTPN1 (PTP1B) were checked in CC. Interacting partners of PTP1B through STRING and hub genes through Cytoscape (MCODE) were identified. Hub genes were subjected to functional enrichment analyses (via Metascape), differential gene expression, copy number variation, and single nucleotide variation analyses (GSCA database). Cancer-related pathways and associated immune infiltrates of the hub genes were checked too. Eleven sweet potato-derived compounds selected through drug likeness (DL) and toxicity filters were explored via molecular docking (AutoDock Vina) to reveal the interactions with PTP1B. Genomic alteration frequency of the PTPN1 was highest in CC compared to all the other TCGA cancers, and a high expression (RNA and protein) is also observed in CC that correlated well to a poor overall survival (OS). Furthermore, PTP1B and related proteins were enriched in different biological processes and signaling pathways related to carcinogenesis including epithelial-mesenchymal transition. Overall, PTP1B identified as a potential target in obesity-linked CC and sweet potato might exert its protective action by targeting the PTP1B. Sweet potato compounds (e.g., pelargonidin and luteolin) interacted with the catalytic P loop and the WPD loop of the PTP1B. Furthermore, MD simulation study ascertained that luteolin has the highest affinity against the PTP1B, whereas pelargonidin and quercetin showed good binding affinity too, thus can be explored further.

Strategies Targeting Protein Tyrosine Phosphatase SHP2 for Cancer Therapy.

The protein tyrosine phosphatase SHP2 encoded by PTPN11 is a promising therapeutic target for cancer therapy, while the multifaceted roles of SHP2 complicate the drug discovery targeting SHP2. Given the biological significance of SHP2, strategies targeting SHP2 have been developed in recent years. To date, eight SHP2 inhibitors have advanced into clinical trials as mono- or combined therapy for treating solid tumors or adaptive resistant cancers. In this Perspective, we briefly summarize the strategies targeting SHP2 including inhibitors, activators, and proteolysis-targeting chimera (PROTAC) degraders. Besides, targeting the protein-protein interactions between SHP2 and other adaptor proteins is also discussed. Finally, we also highlight the target- and pathway-dependent combination strategies of SHP2 for cancer therapy. This Perspective may provide a timely and updated overview on the strategies targeting SHP2 for cancer therapy.

MiR-647 inhibits hepatocellular carcinoma cell progression by targeting protein tyrosine phosphatase receptor type F

ABSTRACT Hepatocellular carcinoma (HCC) is a kind of malignant tumor derived from hepatocytes and hepatobiliary cells, and its occurrence is prevalent worldwide. Although medical technology is developing rapidly, the therapeutic efficacy of HCC is still poor. Emerging evidence manifests that microRNAs (miRNAs) play a crucial role in various cancers and have been regarded as cancer suppressor gene. However, the regulatory mechanisms mediated by miR-647 involved in HCC remain unclear. Hence, to clarify the regulatory mechanisms mediated by miR-647 in HCC, we studied the independent effects of miR-647 and explored protein tyrosine phosphatase receptor type F (PTPRF) in the constructed HCC cell line (HCV-huh7.5). Thereafter, we used dual-luciferase gene reporting and Western blot to investigate the relationship between PTPRF and miR-647. Furthermore, we studied the mechanism of miR-647 on PTPRF in HCV-huh7.5. We found that miR-647 could not only promote the proliferation and invasion of HCV-huh7.5 cells but also facilitate cell migration, while PTPRF has the opposite effect. Besides, the results of cell function experiment implied that the overexpression of miR-647 or inhibition of PTPFRF remarkably influenced the Erk signaling pathway, which could regulate cell proliferation, migration, and invasion. In addition, the dual luciferase reporting identified PTPRF as a direct target of miR-647. We further demonstrated that miR-647 inhibitor or PTPRF knockdown administration boosted HCV-huh7.5 cell proliferation, migration, and invasion by targeting PTPRF. These findings provided clues for the mechanism of miR-647 in promoting the biology of HCV-huh7.5 cells by inhibiting the expression level of PTPRF.

Downregulation of Erythrocyte miR-210 Induces Endothelial Dysfunction in Type 2 Diabetes.

Red blood cells (RBC) act as mediators of vascular injury in type 2 diabetes mellitus (T2DM). miR-210 plays a protective role in cardiovascular homeostasis and is decreased in whole blood of T2DM mice. We hypothesized that downregulation of RBC miR-210 induces endothelial dysfunction in T2DM. RBC were coincubated with arteries and endothelial cells ex vivo and transfused in vivo to identify the role of miR-210 and its target protein tyrosine phosphatase 1B (PTP1B) in endothelial dysfunction. RBC from patients with T2DM and diabetic rodents induced endothelial dysfunction ex vivo and in vivo. miR-210 levels were lower in human RBC from patients with T2DM (T2DM RBC) than in RBC from healthy subjects. Transfection of miR-210 in human T2DM RBC rescued endothelial function, whereas miR-210 inhibition in healthy subjects RBC or RBC from miR-210 knockout mice impaired endothelial function. Human T2DM RBC decreased miR-210 expression in endothelial cells. miR-210 expression in carotid artery plaques was lower in T2DM patients than in patients without diabetes. Endothelial dysfunction induced by downregulated RBC miR-210 involved PTP1B and reactive oxygen species. miR-210 mimic attenuated endothelial dysfunction induced by RBC via downregulating vascular PTP1B and oxidative stress in diabetic mice in vivo. These data reveal that the downregulation of RBC miR-210 is a novel mechanism driving the development of endothelial dysfunction in T2DM.

Discovery of novel and selective inhibitors targeting protein tyrosine phosphatase 1B (PTP1B): Virtual screening and molecular dynamic simulation

Protein tyrosine phosphatase 1B (PTP1B) is a promising target for Type II diabetes, obesity, and cancer therapeutics. However, capturing selectivity over T cell protein tyrosine phosphatase (TCPTP) is key to PTP1B inhibitor discovery. Current studies demonstrate that the phosphotyrosine (pTyr) binding site confers selectivity to inhibitors. To identify novel selective inhibitors of PTP1B, drugs in the DrugBank were docked into the active and pTyr site using virtual docking tools. The most suitable drugs were selected based on their docking scores, similarity, and visual results before molecular dynamic simulations were performed. A combination of virtual screening and molecular dynamic simulation approaches indicated that five drugs (DB03558, DB05123, DB03310, DB05446, DB03530) targeting the active and second pTyr binding site of PTP1B could be potential selective inhibitors. This study showed that the hit drugs (experimental, research, and approved) could serve as potential selectivity PTP1B inhibitors and as useful treatments for diabetes and cancer. The hit drugs can be experimentally validated via in vitro molecular testing and in vivo animal testing; alternatively, they can be included in ongoing clinical trials. In addition, more effective molecules can be designed by derivatizing these drugs.

Discovery of inhibitors targeting protein tyrosine phosphatase 1B using acombined virtual screening approach.

Protein tyrosine phosphatase 1B (PTP1B) acts as a therapeutic target for type 2 diabetes. However, the major challenges of PTP1B drug discovery are the poor selectivity and the weak oral bioavailability. In this study, we performed a combined virtual screening approach including multicomplex pharmacophore, molecular docking-based screening, van der Waals energy normalization, pose scaling factor, ADMET evaluation, and molecular dynamics simulation to select PTP1B inhibitors from three databases (PubChem, ChEMBL, and ZINC). We identified three potential PTP1B inhibitors, compounds 1, 4, and 5, with favorable binding energy and good oral bioavailability. The energetic and geometrical analyses show that the three compounds are stably bound to PTP1B, via occupying both the catalytic site (site A) and the proximal noncatalytic site (site B or C). Such occupancy may improve the selectivity. This work not only provided a feasible virtual screening protocol, but also suggested three potential PTP1B inhibitors for the treatment of type 2 diabetes.