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1.
N Engl J Med ; 387(12): 1089-1098, 2022 09 22.
Article in English | MEDLINE | ID: covidwho-2036975

ABSTRACT

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain. METHODS: We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis. RESULTS: Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.).


Subject(s)
Heart Failure , Sodium-Glucose Transporter 2 Inhibitors , Stroke Volume , Ventricular Function, Left , Benzhydryl Compounds/adverse effects , Benzhydryl Compounds/therapeutic use , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Glucosides/adverse effects , Glucosides/therapeutic use , Heart Failure/complications , Heart Failure/drug therapy , Heart Failure/mortality , Heart Failure/physiopathology , Humans , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Stroke Volume/drug effects , Ventricular Function, Left/drug effects
2.
Molecules ; 27(17)2022 Aug 24.
Article in English | MEDLINE | ID: covidwho-2023941

ABSTRACT

Flavonoids are biologically active natural products of great interest for their potential applications in functional foods and pharmaceuticals. A hesperetin-7-O-glucoside inclusion complex with ß-cyclodextrin (HEPT7G/ßCD; SunActive® HCD) was formulated via the controlled enzymatic hydrolysis of hesperidin with naringinase enzyme. The conversion rate was nearly 98%, estimated using high-performance liquid chromatography analysis. The objective of this study was to investigate the stability, solubility, and spectroscopic features of the HEPT7G/ßCD inclusion complex using Fourier-transform infrared (FTIR), Raman, ultraviolet-visible absorption (UV-vis), 1H- and 13C- nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), liquid chromatography/mass spectroscopy (LC-MS), scanning electron microscopy (SEM), and powdered X-ray diffraction (PXRD) spectroscopic techniques including zeta potential, Job's plot, and phase solubility measurements. The effects of complexation on the profiles of supramolecular interactions in analytic features, especially the chemical shifts of ß-CD protons in the presence of the HEPT7G moiety, were evaluated. The stoichiometric ratio, stability, and solubility constants (binding affinity) describe the extent of complexation of a soluble complex in 1:1 stoichiometry that exhibits a greater affinity and fits better into the ß-CD inner cavity. The NMR spectroscopy results identified two different configurations of the HEPT7G moiety and revealed that the HEPT7G/ßCD inclusion complex has both -2S and -2R stereoisomers of hesperetin-7-O-glucoside possibly in the -2S/-2R epimeric ratio of 1/1.43 (i.e., -2S: 41.1% and -2R: 58.9%). The study indicated that encapsulation of the HEPT7G moiety in ß-CD is complete inclusion, wherein both ends of HEPT7G are included in the ß-CD inner hydrophobic cavity. The results showed that the water solubility and thermal stability of HEPT7G were apparently increased in the inclusion complex with ß-CD. This could potentially lead to increased bioavailability of HEPT7G and enhanced health benefits of this flavonoid.


Subject(s)
Hesperidin , beta-Cyclodextrins , Calorimetry, Differential Scanning , Flavonoids/chemistry , Glucosides , Protons , Solubility , Spectroscopy, Fourier Transform Infrared/methods , X-Ray Diffraction , beta-Cyclodextrins/chemistry
3.
Microb Biotechnol ; 15(9): 2401-2410, 2022 09.
Article in English | MEDLINE | ID: covidwho-2019055

ABSTRACT

The natural flavonoids luteolin and luteoloside have anti-bacterial, anti-inflammatory, anti-oxidant, anti-tumour, hypolipidemic, cholesterol lowering and neuroprotective effects, but their poor water solubility limits their application in industrial production and the pharmaceutical industry. In this study, luteolin-7-O-ß-(6″-O-succinyl)-d-glucoside, a new compound that was prepared by succinyl glycosylation of luteolin by the organic solvent tolerant bacterium Bacillus amyloliquefaciens FJ18 in an 8.0% DMSO (v/v) system, was obtained and identified. Its greater water solubility (2293 times that of luteolin and 12 232 times that of luteoloside) provides the solution to the application problems of luteolin and luteoloside. The conversion rate of luteolin (1.0 g l-1 ) was almost 100% at 24 h, while the yield of luteolin-7-O-ß-(6″-O-succinyl)-d-glucoside reached 76.2%. In experiments involving the oxygen glucose deprivation/reoxygenation injury model of mouse hippocampal neuron cells, the cell viability was significantly improved with luteolin-7-O-ß-(6″-O-succinyl)-d-glucoside dosing, and the expressions of the anti-oxidant enzyme HO-1 in the nucleus increased, providing a neuroprotective effect for ischemic cerebral cells. The availability of biosynthetic luteolin-7-O-ß-(6″-O-succinyl)-d-glucoside, which is expected to replace luteolin and luteoloside, would effectively expand the clinical application value of luteolin derivatives.


Subject(s)
Luteolin , Neuroprotective Agents , Animals , Anti-Inflammatory Agents , Antioxidants , Glucosides , Luteolin/pharmacology , Mice , Neuroprotective Agents/pharmacology , Solubility , Water
4.
Medicina (Kaunas) ; 58(9)2022 Aug 27.
Article in English | MEDLINE | ID: covidwho-2006132

ABSTRACT

Background and Objectives: Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of cardiovascular disease. Arterial stiffness is an independent prognostic marker for cardiovascular disease development. We aimed at determining the effect of two different sodium-glucose co-transporter-2 (SGLT-2) inhibitors on ambulatory arterial stiffness in individuals with T2DM. Materials and Methods: In this single-center, single-arm, prospective study performed from January 2020 to August 2021, we planned to enroll adult subjects with T2DM and stable antidiabetic and antihypertensive treatment, assigned either to empagliflozin or dapagliflozin for 6 months. All eligible subjects underwent ambulatory blood pressure monitoring. We set as the primary efficacy outcome the change in ambulatory pulse wave velocity (PWV) from baseline to week 24. Results: We finally enrolled 46 diabetic subjects, with a mean age of 62.89 (8.53) years and mean T2DM duration of 9.72 (6.37) years. Thirty patients received dapagliflozin, while sixteen patients received empagliflozin. Due to COVID-19 pandemic restrictive measures during the study, the mean follow-up period extended from 6 months to 9.98 (3.27) months. Regarding the prespecified primary efficacy outcome, we found that the SGLT-2 inhibitor treatment did not have a significant effect on PWV (p = 0.65). Prior history of cardiovascular disease did not significantly affect the observed effects. Other indices of arterial stiffness, such as augmentation index and central pulse pressure, were not significantly affected, neither by empagliflozin nor by dapagliflozin. Conclusions: SGLT-2 inhibitor treatment with empagliflozin or dapagliflozin in subjects with T2DM failed to improve ambulatory PWV over a mean follow-up of 10 months. Registration number: ISRCTN88851713.


Subject(s)
COVID-19 , Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Sodium-Glucose Transporter 2 Inhibitors , Symporters , Vascular Stiffness , Antihypertensive Agents/pharmacology , Benzhydryl Compounds , Blood Pressure Monitoring, Ambulatory , Cardiovascular Diseases/chemically induced , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Glucose , Glucosides , Humans , Hypoglycemic Agents/adverse effects , Middle Aged , Morbidity , Pandemics , Prospective Studies , Pulse Wave Analysis , Sodium , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Symporters/pharmacology , Treatment Outcome
5.
ESC Heart Fail ; 9(4): 2233-2238, 2022 08.
Article in English | MEDLINE | ID: covidwho-1940839

ABSTRACT

AIMS: In this prospective, placebo-controlled, double-blind, exploratory study, we examined early and more delayed effects of empagliflozin treatment on haemodynamic parameters (primary endpoint: cardiac output) and kidney function including parameters of acute kidney injury (AKI) in patients with acute decompensated heart failure (HF). METHODS AND RESULTS: Patients with acute decompensated HF with or without diabetes were randomized to empagliflozin 10 mg or placebo for 30 days. Haemodynamic, laboratory, and urinary parameters were assessed after 6 h, 1 day, 3 days, 7 days, and 30 days of treatment. Median time between hospital admission and randomization was 72 h. Baseline characteristics were not different in the empagliflozin (n = 10) and placebo (n = 9) groups. Empagliflozin led to a significant increase in urinary glucose excretion throughout the study (baseline: 37 ± 15 mg/24 h; Day 1: 14 565 ± 8663 mg/24 h; P = 0.001). Empagliflozin did not affect the primary endpoint of cardiac index or on systemic vascular resistance index at any time point. However, empagliflozin significantly reduced parameters of AKI (urinary TIMP-2 and IGFBP7 by NephroCheck® as indicators of tubular kidney damage), which became significant after 3 days of treatment [placebo: 1.1 ± 1.1 (ng/mL)2 /1000; empagliflozin: 0.3 ± 0.2 (ng/mL)2 /1000; P = 0.02] and remained significant at the 7 day time point [placebo: 2.5 ± 3.8 (ng/mL)2 /1000; empagliflozin: 0.3 ± 0.2 (ng/mL)2 /1000; P = 0.003]. CONCLUSIONS: In this study, empagliflozin treatment did not affect haemodynamic parameters but significantly reduced markers of tubular injury in patients with acute decompensated HF.


Subject(s)
Acute Kidney Injury , Heart Failure , Acute Kidney Injury/drug therapy , Benzhydryl Compounds , Biomarkers , Glucosides/therapeutic use , Heart Failure/complications , Heart Failure/drug therapy , Humans , Prospective Studies
6.
Biomed Pharmacother ; 153: 113414, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1936094

ABSTRACT

Targeting macrophage M1 polarization is a promising strategy with fewer detrimental effects in COVID-19 curation. Phenylethanoid glycosides (PhGs) of Cistanche tubulosa are a botanical drug to possess various anti-inflammation-related functions, such as immunomodulating, hepatoprotective or neuroprotective functions, whereas their anti-inflammatory activity is rarely understood. A search into their anti-inflammatory characteristics led to the isolation of 49 PhGs along with 15 new PhGs. Their inhibitory effects against M1 polarization induced by LPS plus IFN-γ were explored in RAW264.7 macrophages. Of these PhGs, tubuloside B (Tub B) exerted substantial NO scavenging effect both in chemical- and cell-based assays, and it inhibited massive production of cytokines and chemokines. Tub B decreased ERK1/2 phosphorylation via direct binding and inhibited the MAPK signaling pathway. Tub B also directly binded to Mob1 protein, thereby increased the stability and level of Mob1 protein by inhibiting ubiquitinated degradation. Mob1 was pivotal for the anti-inflammatory activity of Tub B, and it acted independently of the canonical Hippo-YAP pathway. Moreover, ERK1/2 and Mob1 also had a synergic effect on modulating the inflammatory response. Finally, these effects of Tub B were verified in mice with LPS-induced systemic inflammatory response syndrome. Taken together, these results indicated that Tub B acted as a promising agent against M1 macrophage activation by synergistically targeting ERK1/2 and Mob1, and that it may potentially be a drug candidate to prevent/treat inflammatory diseases, especially in COVID-19.


Subject(s)
COVID-19 , Cistanche , Animals , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/pharmacology , COVID-19/drug therapy , Glucosides , Glycosides/pharmacology , Intracellular Signaling Peptides and Proteins/metabolism , Lipopolysaccharides/metabolism , Lipopolysaccharides/pharmacology , MAP Kinase Signaling System , Macrophage Activation , Macrophages/metabolism , Mice , Plant Extracts/pharmacology
7.
Nutrients ; 14(13)2022 Jun 30.
Article in English | MEDLINE | ID: covidwho-1917652

ABSTRACT

Black rice is a functional food that is high in anthocyanin content, primarily C3G and P3G. It possesses nutraceutical properties that exhibit a range of beneficial effects on human health. Currently, the spike glycoprotein S1 subunit of SARS-CoV-2 (SP) has been reported for its contribution to pathological inflammatory responses in targeting lung tissue and innate immune cells during COVID-19 infection and in the long-COVID phenomenon. Our objectives focused on the health benefits of the C3G and P3G-rich fraction of black rice germ and bran (BR extract) on the inhibition of inflammatory responses induced by SP, as well as the inhibition of NF-kB activation and the NLRP3 inflammasome pathway in an in vitro model. In this study, BR extract was identified for its active anthocyanins, C3G and P3G, using the HPLC technique. A549-lung cells and differentiated THP-1 macrophages were treated with BR extract, C3G, or P3G prior to exposure to 100 ng/mL of SP. Their anti-inflammatory properties were then determined. BR extract at concentrations of 12.5-100 µg/mL exhibited anti-inflammation activity for both A549 and THP-1 cells through the significant suppression of NLRP3, IL-1ß, and IL-18 inflammatory gene expressions and IL-6, IL-1ß, and IL-18 cytokine secretions in a dose-dependent manner (p < 0.05). It was determined that both cell lines, C3G and P3G (at 1.25-10 µg/mL), were compatibly responsible for the significant inhibition of SP-induced inflammatory responses for both gene and protein levels (p < 0.05). With regard to the anti-inflammation mechanism, BR extract, C3G, and P3G could attenuate SP-induced inflammation via counteraction with NF-kB activation and downregulation of the inflammasome-dependent inflammatory pathway proteins (NLRP3, ASC, and capase-1). Overall, the protective effects of anthocyanins obtained from black rice germ and bran can be employed in potentially preventive strategies that use pigmented rice against the long-term sequelae of COVID-19 infection.


Subject(s)
COVID-19 , Oryza , Anthocyanins/pharmacology , COVID-19/complications , Glucosides/pharmacology , Humans , Inflammasomes , Interleukin-18 , Lung/metabolism , Macrophages/metabolism , NF-kappa B/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Oryza/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
8.
Molecules ; 27(13)2022 Jun 22.
Article in English | MEDLINE | ID: covidwho-1911485

ABSTRACT

Moringa oleifera (M. oleifera) leaves are rich in nutrients and antioxidant compounds that can be consumed to prevent and overcome malnutrition. The water infusion of its leaf is the easiest way to prepare the herbal drink. So far, no information is available on the antioxidant, antimutagenic, and antivirus capacities of this infusion. This study aimed to determine the composition of the bioactive compounds in M. oleifera leaf infusion, measuring for antioxidant and antimutagenic activity, and evaluating any ability to inhibit the SARS-CoV-2 main protease (Mpro). The first two objectives were carried out in vitro. The third objective was carried out in silico. The phytochemical analysis of M. oleifera leaf infusion was carried out using liquid chromatography-mass spectrometry (LC-MS). Antioxidant activity was measured as a factor of the presence of the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). The antimutagenicity of M. oleifera leaf powder infusion was measured using the plasmid pBR322 (treated free radical). The interaction between bioactive compounds and Mpro of SARS-CoV-2 was analyzed via molecular docking. The totals of phenolic compound and flavonoid compound from M. oleifera leaf infusion were 1.780 ± 5.00 µg gallic acid equivalent/g (µg GAE/g) and 322.91 ± 0.98 µg quercetin equivalent/g (µg QE/g), respectively. The five main bioactive compounds involved in the infusion were detected by LC-MS. Three of these were flavonoid glucosides, namely quercetin 3-O-glucoside, kaempferol 3-O-neohesperidoside, and kaempferol 3-α-L-dirhamnosyl-(1→4)-ß-D-glucopyranoside. The other two compounds were undulatoside A, which belongs to chromone-derived flavonoids, and gentiatibetine, which belongs to alkaloids. The antioxidant activity of M. oleifera leaf infusion was IC50 8.19 ± 0.005 µg/mL, which is stronger than the standard butylated hydroxytoluene (BHT) IC50 11.60 ± 0.30 µg/mL. The infusion has an antimutagenic effect and therefore protects against deoxyribonucleic acid (DNA) damage. In silico studies showed that the five main bioactive compounds have an antiviral capacity. There were strong energy bonds between Mpro molecules and gentiatibetine, quercetin, undulatoside A, kaempferol 3-o-neohesperidoside, and quercetin 3-O-glucoside. Their binding energy values are -5.1, -7.5, -7.7, -5.7, and -8.2 kcal/mol, respectively. Their antioxidant activity, ability to maintain DNA integrity, and antimutagenic properties were more potent than the positive controls. It can be concluded that leaf infusion of M. oleifera does provide a promising herbal drink with good antioxidant, antimutagenic, and antivirus capacities.


Subject(s)
COVID-19 , Moringa oleifera , Antioxidants/chemistry , Antiviral Agents/analysis , Antiviral Agents/pharmacology , COVID-19/drug therapy , DNA/analysis , Flavonoids/chemistry , Glucosides/analysis , Molecular Docking Simulation , Moringa oleifera/chemistry , Phytochemicals/analysis , Phytochemicals/pharmacology , Plant Extracts/chemistry , Plant Leaves/chemistry , Quercetin/analysis , Quercetin/pharmacology , SARS-CoV-2
9.
Biomed Pharmacother ; 153: 113296, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1894813

ABSTRACT

Acteoside (AC), a phenylpropanoid glycoside isolated from many dicotyledonous plants, has been demonstrated various pharmacological activities, including anti-oxidation, anti-inflammation, anti-cancer, neuroprotection, cardiovascular protection, anti-diabetes, bone and cartilage protection, hepatoprotection, and anti-microorganism. However, AC has a poor bioavailability, which can be potentially improved by different strategies. The health-promoting characteristics of AC can be attributed to its mediation in many signaling pathways, such as MAPK, NF-κB, PI3K/AKT, TGFß/Smad, and AMPK/mTOR. Interestingly, docking simulation study indicates that AC can be an effective candidate to inhibit the activity of SARS-CoV2 main protease and protect against COVID-19. Many clinical trials for AC have been investigated, and it shows great potentials in drug development.


Subject(s)
COVID-19 , Phosphatidylinositol 3-Kinases , COVID-19/drug therapy , Glucosides , Humans , NF-kappa B/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Polyphenols , RNA, Viral , SARS-CoV-2
12.
Colloids Surf B Biointerfaces ; 214: 112465, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1763665

ABSTRACT

Despite their importance there is little knowledge at the atomic scale on the interactions between fragments of SARS-CoV-2 and inorganic materials. Such knowledge is important to understand the survival of the virus at surfaces and for the development of antiviral materials. Here is reported a study of the interactions between glucoside monomers of the tip of the S1 subunit of SARS-CoV-2 spike protein with dry and wet surfaces of CuO and Cu, performed with dispersion corrected density functional theory-DFT. The three glucoside monomers that constitute the tip of S1: 6VSB, 6VXX and 6X6P, were adsorbed onto dry and wet CuO(111) and Cu(110) with different orientations and surface alignments. There are large differences-of up to 1.3 eV-in binding energies between these monomers and the surfaces. These differences depend on: the type of surface; if the surface is wet or dry; if the glucosidic O-atom points towards or away from the surfaces; and to a smaller extent on the surface alignment of the monomers. All monomers bind strongly to the surfaces via molecular adsorption that does not involve bond breaking in the monomers at this stage. 6VSB has the larger adsorption energies-that reach 2.2 eV-due to its larger dipole moment. Both materials bind the monomers more strongly when their surfaces are dry. At Cu(110) the bonds are on average 1 eV stronger when the surface is dry when compared to wet. The difference between dry and wet CuO(111) is smaller, in the order of 0.2 eV. Overall, it is here shown that the stability of the monomers of the tip of the spike protein of the virus is very different at different surfaces. For a given surface the larger binding energies in dry conditions could explain the differences in the surface stability of the spike protein depending on the presence of moisture.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Copper , Glucosides , Humans , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
13.
Am J Chin Med ; 50(2): 351-369, 2022.
Article in English | MEDLINE | ID: covidwho-1723921

ABSTRACT

The development of anti-COVID-19 drugs has become the top priority since the outbreak of the epidemic, and Traditional Chinese medicine plays an important role in reducing mortality. Here, hesperidin and its glycosylation product, glucosyl hesperidin were selected to determine their antiviral activity against SARS-CoV-2 due to their structural specificity as reported. To be specific, their binding ability with ACE2, M, S, RBD and N proteins were verified with both in silico and wet lab methods, i.e., molecular docking and binding affinity tests, including biolayer interferometry assay (BLI) and isothermal titration calorimetry assay (ITC). Moreover, systematic pharmacological analysis was conducted to reveal their pharmacological mechanism in treating COVID-19. Finally, their antiviral activity against SARS-CoV-2 was determined in vitro in a biosafety level 3 (BSL3) laboratory. The results demonstrated their outstanding binding affinity with ACE2, M, S and RBD proteins, while showed barely unobserved binding with N protein, indicating their key roles in influencing the invasion and early replication phase of SARS-CoV-2. In addition, both hesperidin and glucosyl hesperidin were shown to have a great impact on immune, inflammation and virus infection induced by COVID-19 according to the systematic pharmacological analysis. Moreover, the IC50s of hesperidin and glucosyl hesperidin against SARS-CoV-2 were further determined (51.5 [Formula: see text]M and 5.5 mM, respectively) with cell-based in vitro assay, suggesting their great anti-SARS-CoV-2 activity. All in all, present research was the first to verify the binding ability of hesperidin and glucosyl hesperidin with SARS-CoV-2 proteins with both in silico and wet-lab methods and proposed the possibility of applying hesperidin and glucosyl hesperidin to treat COVID-19.


Subject(s)
COVID-19 , Hesperidin , Antiviral Agents/pharmacology , COVID-19/drug therapy , Computational Biology , Glucosides , Hesperidin/analogs & derivatives , Hesperidin/pharmacology , Humans , Molecular Docking Simulation , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
14.
Int J Mol Sci ; 23(5)2022 Feb 27.
Article in English | MEDLINE | ID: covidwho-1715407

ABSTRACT

The overall impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on our society is unprecedented. The identification of small natural ligands that could prevent the entry and/or replication of the coronavirus remains a pertinent approach to fight the coronavirus disease (COVID-19) pandemic. Previously, we showed that the phenolic compounds corilagin and 1,3,6-tri-O-galloyl-ß-D-glucose (TGG) inhibit the interaction between the SARS-CoV-2 spike protein receptor binding domain (RBD) and angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 target receptor on the cell membrane of the host organism. Building on these promising results, we now assess the effects of these phenolic ligands on two other crucial targets involved in SARS-CoV-2 cell entry and replication, respectively: transmembrane protease serine 2 (TMPRSS2) and 3-chymotrypsin like protease (3CLpro) inhibitors. Since corilagin, TGG, and tannic acid (TA) share many physicochemical and structural properties, we investigate the binding of TA to these targets. In this work, a combination of experimental methods (biochemical inhibition assays, surface plasmon resonance, and quartz crystal microbalance with dissipation monitoring) confirms the potential role of TA in the prevention of SARS-CoV-2 infectivity through the inhibition of extracellular RBD/ACE2 interactions and TMPRSS2 and 3CLpro activity. Moreover, molecular docking prediction followed by dynamic simulation and molecular mechanics Poisson-Boltzmann surface area (MMPBSA) free energy calculation also shows that TA binds to RBD, TMPRSS2, and 3CLpro with higher affinities than TGG and corilagin. Overall, these results suggest that naturally occurring TA is a promising candidate to prevent and inhibit the infectivity of SARS-CoV-2.


Subject(s)
COVID-19/metabolism , Molecular Docking Simulation , SARS-CoV-2/metabolism , Serine Endopeptidases/metabolism , Tannins/pharmacology , Algorithms , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/epidemiology , COVID-19/virology , Coronavirus 3C Proteases , Glucosides/chemistry , Glucosides/metabolism , Glucosides/pharmacology , Humans , Hydrolyzable Tannins/chemistry , Hydrolyzable Tannins/metabolism , Hydrolyzable Tannins/pharmacology , Kinetics , Pandemics/prevention & control , Protein Binding/drug effects , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , Surface Plasmon Resonance , Tannins/chemistry , Tannins/metabolism , Virus Internalization/drug effects
15.
Mol Biol Rep ; 49(3): 2321-2324, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1664478

ABSTRACT

Numerous studies demonstrate parallels between CVD, type 2 diabetes mellitus (T2DM) and COVID-19 pathology, which accentuate pre-existing complications in patients infected with COVID-19 and potentially exacerbate the infection course. Antidiabetic drugs such as sodium-glucose transporter-2 (SGLT-2) inhibitors have garnered substantial attention recently due to their efficacy in reducing the severity of cardiorenal disease. The effect of SGLT-2 inhibitors in patients with COVID-19 remains unclear particularly since SGLT-2 inhibitors contribute to altering the RAAS cascade activity, which includes ACE-2, the major cell entry receptor for SARS-CoV2. A study, DARE-19, was carried out to unveil the effects of SGLT-2 inhibitor treatment on comorbid disease complications and concomitant COVID-19 outcomes and demonstrated no statistical significance. However, the need for further studies is essential to provide conclusive clinical findings.


Subject(s)
Benzhydryl Compounds/therapeutic use , COVID-19/complications , Glucosides/therapeutic use , Renin-Angiotensin System/drug effects , Respiratory Insufficiency/drug therapy , SARS-CoV-2 , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Angiotensin-Converting Enzyme 2/physiology , Clinical Trials, Phase III as Topic , Double-Blind Method , Drug Repositioning , Heart Diseases/prevention & control , Humans , Kidney Diseases/prevention & control , Mitochondria/drug effects , Multicenter Studies as Topic , Oxidative Stress/drug effects , Randomized Controlled Trials as Topic , Receptors, Virus/physiology , Respiratory Insufficiency/etiology , Sodium-Glucose Transporter 2/physiology , Sodium-Glucose Transporter 2 Inhibitors/pharmacology
16.
Bioengineered ; 13(2): 3350-3361, 2022 02.
Article in English | MEDLINE | ID: covidwho-1632167

ABSTRACT

The COVID-19 new variants spread rapidly all over the world, and until now scientists strive to find virus-specific antivirals for its treatment. The main protease of SARS-CoV-2 (Mpro) exhibits high structural and sequence homology to main protease of SARS-CoV (93.23% sequence identity), and their sequence alignment indicated 12 mutated/variant residues. The sequence alignment of SARS-CoV-2 main protease led to identification of only one mutated/variant residue with no significant role in its enzymatic process. Therefore, Mpro was considered as a high-profile drug target in anti-SARS-CoV-2 drug discovery. Apigenin analogues to COVID-19 main protease binding were evaluated. The detailed interactions between the analogues of Apigenin and SARS-CoV-2 Mpro inhibitors were determined as hydrogen bonds, electronic bonds and hydrophobic interactions. The binding energies obtained from the molecular docking of Mpro with Boceprevir, Apigenin, Apigenin 7-glucoside-4'-p-coumarate, Apigenin 7-glucoside-4'-trans-caffeate and Apigenin 7-O-beta-d-glucoside (Cosmosiin) were found to be -6.6, -7.2, -8.8, -8.7 and -8.0 kcal/mol, respectively. Pharmacokinetic parameters and toxicological characteristics obtained by computational techniques and Virtual ADME studies of the Apigenin analogues confirmed that the Apigenin 7-glucoside-4'-p-coumarate is the best candidate for SARS-CoV-2 Mpro inhibition.


Subject(s)
Antiviral Agents/pharmacology , Apigenin/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Amino Acid Sequence , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Apigenin/chemistry , Apigenin/pharmacokinetics , Bioengineering , COVID-19/virology , Computer Simulation , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/genetics , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacokinetics , Drug Evaluation, Preclinical , Glucosides/chemistry , Glucosides/pharmacokinetics , Glucosides/pharmacology , Humans , Molecular Docking Simulation , Phytotherapy , Protein Domains , SARS-CoV-2/genetics
17.
Lancet Diabetes Endocrinol ; 10(2): 97-98, 2022 02.
Article in English | MEDLINE | ID: covidwho-1569157
19.
Lancet Diabetes Endocrinol ; 9(9): 586-594, 2021 09.
Article in English | MEDLINE | ID: covidwho-1545532

ABSTRACT

BACKGROUND: COVID-19 can lead to multiorgan failure. Dapagliflozin, a SGLT2 inhibitor, has significant protective benefits for the heart and kidney. We aimed to see whether this agent might provide organ protection in patients with COVID-19 by affecting processes dysregulated during acute illness. METHODS: DARE-19 was a randomised, double-blind, placebo-controlled trial of patients hospitalised with COVID-19 and with at least one cardiometabolic risk factor (ie, hypertension, type 2 diabetes, atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease). Patients critically ill at screening were excluded. Patients were randomly assigned 1:1 to dapagliflozin (10 mg daily orally) or matched placebo for 30 days. Dual primary outcomes were assessed in the intention-to-treat population: the outcome of prevention (time to new or worsened organ dysfunction or death), and the hierarchial composite outcome of recovery (change in clinical status by day 30). Safety outcomes, in patients who received at least one study medication dose, included serious adverse events, adverse events leading to discontinuation, and adverse events of interest. This study is registered with ClinicalTrials.gov, NCT04350593. FINDINGS: Between April 22, 2020 and Jan 1, 2021, 1250 patients were randomly assigned with 625 in each group. The primary composite outcome of prevention showed organ dysfunction or death occurred in 70 patients (11·2%) in the dapagliflozin group, and 86 (13·8%) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·58-1·10; p=0·17). For the primary outcome of recovery, 547 patients (87·5%) in the dapagliflozin group and 532 (85·1%) in the placebo group showed clinical status improvement, although this was not statistically significant (win ratio 1·09, 95% CI 0·97-1·22; p=0·14). There were 41 deaths (6·6%) in the dapagliflozin group, and 54 (8·6%) in the placebo group (HR 0·77, 95% CI 0·52-1·16). Serious adverse events were reported in 65 (10·6%) of 613 patients treated with dapagliflozin and in 82 (13·3%) of 616 patients given the placebo. INTERPRETATION: In patients with cardiometabolic risk factors who were hospitalised with COVID-19, treatment with dapagliflozin did not result in a statistically significant risk reduction in organ dysfunction or death, or improvement in clinical recovery, but was well tolerated. FUNDING: AstraZeneca.


Subject(s)
Benzhydryl Compounds/administration & dosage , COVID-19/complications , Cardiometabolic Risk Factors , Glucosides/administration & dosage , Multiple Organ Failure/prevention & control , Sodium-Glucose Transporter 2 Inhibitors/administration & dosage , Aged , Double-Blind Method , Female , Humans , Male , Middle Aged , Multiple Organ Failure/complications , Treatment Outcome
20.
Phys Chem Chem Phys ; 23(27): 14873-14888, 2021 Jul 14.
Article in English | MEDLINE | ID: covidwho-1541260

ABSTRACT

The COVID-19 disease caused by the virus SARS-CoV-2, first detected in December 2019, is still emerging through virus mutations. Although almost under control in some countries due to effective vaccines that are mitigating the worldwide pandemic, the urgency to develop additional vaccines and therapeutic treatments is imperative. In this work, the natural polyphenols corilagin and 1,3,6-tri-O-galloy-ß-d-glucose (TGG) are investigated to determine the structural basis of inhibitor interactions as potential candidates to inhibit SARS-CoV-2 viral entry into target cells. First, the therapeutic potential of the ligands are assessed on the ACE2/wild-type RBD. We first use molecular docking followed by molecular dynamics, to take into account the conformational flexibility that plays a significant role in ligand binding and that cannot be captured using only docking, and then analyze more precisely the affinity of these ligands using MMPBSA binding free energy. We show that both ligands bind to the ACE2/wild-type RBD interface with good affinities which might prevent the ACE2/RBD association. Second, we confirm the potency of these ligands to block the ACE2/RBD association using a combination of surface plasmon resonance and biochemical inhibition assays. These experiments confirm that TGG and, to a lesser extent, corilagin, inhibit the binding of RBD to ACE2. Both experiments and simulations show that the ligands interact preferentially with RBD, while weak binding is observed with ACE2, hence, avoiding potential physiological side-effects induced by the inhibition of ACE2. In addition to the wild-type RBD, we also study numerically three RBD mutations (E484K, N501Y and E484K/N501Y) found in the main SARS-CoV-2 variants of concerns. We find that corilagin could be as effective for RBD/E484K but less effective for the RBD/N501Y and RBD/E484K-N501Y mutants, while TGG strongly binds at relevant locations to all three mutants, demonstrating the significant interest of these molecules as potential inhibitors for variants of SARS-CoV-2.


Subject(s)
Antiviral Agents/chemistry , Gallic Acid/analogs & derivatives , Glucose/analogs & derivatives , Glucosides/chemistry , Hydrolyzable Tannins/chemistry , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Binding Sites , Gallic Acid/chemistry , Glucose/chemistry , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Mutation , Protein Binding/drug effects , Protein Interaction Domains and Motifs/genetics , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
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