Structural Insight into the Design on Oleanolic Acid Derivatives as Potent Protein Tyrosine Phosphatase 1B Inhibitors

Oleanolic acid derivatives act as newer protein tyrosine phosphatase 1B （PTP-1B） inhibitors for type 2 diabetes mellitus （T2DM）. In order to understand the structural requirement of PTP-1B inhibitors, 52 oleanolic acid derivatives were divided into a training set （34 compounds） and a test set （18 compounds）. The highly reliable and predictive 3D-QSAR models were constructed by CoMFA, CoMSIA and topomer CoMFA methods, respectively. The results showed that the cross validated coefficient （q2） and non-cross-validated coefficient （R2） were 0.554 and 0.999 in the CoMFA model, 0.675 and 0.971 in the CoMSIA model, and 0.628 and 0.939 in the topomer CoMFA model, which suggests that three models are robust and have good exterior predictive capabilities. Furthermore, ten novel inhibitors with much higher inhibitory potency were designed. Our design strategy was that （i） the electronegative substituents （Cl, -CH2OH, OH and -CH2Cl） were introduced into the double bond of ring C, （ii） the hydrogen bond acceptor groups （C≡N and N atom）, electronegative groups （C≡N, N atom, -COOH and -COOCH3） and bulky substituents （C6H5N） were connected to the C-3 position, which would result in generating potent and selective PTP-1B inhibitors. We expect that the results in this paper have the potential to facilitate the process of design and to develop new potent PTP-1B inhibitors.

Regulation of cardiac hERG potassium channel by protein tyrosine phosphatase non-receptor type 12, 11 and 6

Background Long QT syndrome(LQTS)is a potentially fatal cardiac ion channel disease.Mutations in the gene encoding cardiac hERG potassium channel are the second most common causes of LQTS.Cardiac hERG potassium channel conducts the rapidly activating delayed rectifier potassium current(Ikr),which is one of the crucial currents in rapid repolarization phase of action potential in human cardiomyocytes.Function of hERG potassium channel is regulated by a variety of signaling pathways,in which phosphorylation and dephosphorylation of tyrosine proteins plays a major role.Previous research has found that non-receptor protein tyrosine phosphatase(PTPN)can interact with hERG potassium channel in cardiac cells.The aims of the present study were to investigate the regulatory effect of protein tyrosine phosphatase non-receptor type 12,11 and 6(PTPN12,PTPN11 and PTPN6)on cardiac hERG potassium channels.Methods HEK-293 cells were transfected with pcDNA3.0-hERG by Lipofectamine 2000 and selected by G418.HEK-293/hERG cells stably expressing hERG protein were then transfected with pcDNA3.1-PTPN12-RFP,pcDNA3.1-PTPN11-EGFP and pcDNA3.1-PTPN6-EGFP,respectively.Forty-eight hours after transfection,immunofluorescence assay and western blot were performed to detect the expression of hERG channel proteins and PTPN proteins.hERG channel currents in hERG alone-expressing group,PTPN12-,PTPN11-and PTPN6-overexpressing groups,as well as inhibitor groups were recorded by patch clamp technique.Results The maximum pulse current densities of PTPN12-,PTPN11-and PTPN6-overexpressing groups were all decreased when compared with hERG alone-expressing group(P<0.05).However,the maximum pulse current densities of inhibitor groups were all increased when compared with PTPN12-,PTPN11-and PTPN6-overexpressing groups,respectively(P<0.05).Conclusions Overexpression of PTPN12,PTPN11 and PTPN6 reduced the current density of hERG potassium channel,while this effect could be reversed by tyrosine phosphatase inhibitors.These results suggested that PTPN12,PTPN11 and PTPN6 negatively regulated hERG potassium channel currents by catalyzing the dephosphorylation process of hERG potassium channels.[S Chin J Cardiol 2021;22(1):38-49]

Novel and emerging diabetes mellitus drug therapies for the type 2 diabetes patient

Type 2 diabetes mellitus is a metabolic disorder of deranged fat, protein and carbohydrate metabolism resulting in hyperglycemia as a result of insulin resistance and inadequate insulin secretion. Although a wide variety of diabetes therapies is available, yet limited efficacy, adverse effects, cost, contraindications, renal dosage adjustments, inflexible dosing schedules and weight gain significantly limit their use. In addition, many patients in the United States fail to meet the therapeutic HbA1c goal of 【 7% set by the American Diabetes Association. As such new and emerging diabetes therapies with different mechanisms of action hope to address some of these drawbacks to improve the patient with type 2 diabetes. This article reviews new and emerging classes, including the sodium-glucosecotransporter-2 inhibitors, 11β-Hydroxysteroid dehydrogenase type 1 inhibitors, glycogen phosphorylase inhibitors; protein tyrosine phosphatase 1B inhibitors, G Protein-Coupled receptor agonists and glucokinase activators. These emerging diabetes agents hold the promise of providing benefit of glucose lowering, weight reduction, low hypoglycemia risk, improve insulin sensitivity, pancreatic β cell preservation, and oral formulation availability. However, further studies are needed to evaluate their safety profile, cardiovascular effects, and efficacy durability in order to determine their role in type 2 diabetes management.

Macrophage-targeted single walled carbon nanotubes stimulate phagocytosis via pH-dependent drug release

Atherosclerotic cardiovascular disease is the leading cause of mortality in the world.A driving feature of atherosclerotic plaque formation is dysfunctional efferocytosis.Because the“don’t eat me”molecule CD47 is upregulated in atherosclerotic plaque cores,CD47-blocking strategies can stimulate the efferocytic clearance of apoptotic cells and thereby help prevent the progression of plaque buildup.However,these therapies are generally costly and,in clinical and murine trials,they have resulted in side effects including anemia and reticulocytosis.Here,we developed and characterized an intracellular phagocytosis-stimulating treatment in the CD47-SIRPαpathway.We loaded a novel monocyte/macrophage-selective nanoparticle carrier system with a small molecule enzymatic inhibitor that is released in a pH-dependent manner to stimulate macrophage efferocytosis of apoptotic cell debris via the CD47-SIRPαsignaling pathway.We demonstrated that single-walled carbon nanotubes(SWNTs)can selectively deliver tyrosine phosphatase inhibitor 1(TPI)intracellularly to macrophages,which potently stimulates efferocytosis,and chemically characterized the nanocarrier.Thus,SWNT-delivered TPI can stimulate macrophage efferocytosis,with the potential to reduce or prevent atherosclerotic disease.