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1.
Molecules ; 27(5)2022 Mar 07.
Article in English | MEDLINE | ID: covidwho-1732132

ABSTRACT

The COVID-19 pandemic has led to the search for new molecules with antiviral activity against SARS-CoV-2. The entry of the virus into the cell is one of the main targets for inhibiting SARS-CoV-2 infection. Natural products are an important source of new therapeutic alternatives against diseases. Pseudotyped viruses allow the study of SARS-CoV-2 viral entry inhibitors, and due to their simplicity, they allow the screening of a large number of antiviral candidates in Biosafety Level 2 facilities. We used pseudotyped HIV-1 with the D614G SARS-CoV-2 spike glycoprotein to test its ability to infect ACE2-expressing HEK 293T cells in the presence of diverse natural products, including 21 plant extracts, 7 essential oils, and 13 compounds from plants and fungi. The 50% cytotoxic concentration (CC50) was evaluated using the resazurin method. From these analyses, we determined the inhibitory activity of the extract of Stachytarpheta cayennensis, which had a half-maximal inhibitory concentration (IC50) of 91.65 µg/mL, a CC50 of 693.5 µg/mL, and a selectivity index (SI) of 7.57, indicating its potential use as an inhibitor of SARS-CoV-2 entry. Moreover, our work indicates the usefulness of the pseudotyped-virus system in the screening of SARS-CoV-2 entry inhibitors.


Subject(s)
Antiviral Agents/pharmacology , Biological Products/chemistry , Virus Internalization/drug effects , Actinobacteria/chemistry , Actinobacteria/metabolism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Biological Products/metabolism , Biological Products/pharmacology , Biological Products/therapeutic use , COVID-19/drug therapy , COVID-19/virology , HEK293 Cells , High-Throughput Screening Assays/methods , Humans , Oils, Volatile/chemistry , Oils, Volatile/pharmacology , Oils, Volatile/therapeutic use , Plant Extracts/chemistry , Plant Extracts/metabolism , Plant Extracts/pharmacology , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism
2.
Viruses ; 13(10)2021 09 23.
Article in English | MEDLINE | ID: covidwho-1438743

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19). The availability of effective and well-tolerated antiviral drugs for the treatment of COVID-19 patients is still very limited. Traditional herbal medicines elicit antiviral activity against various viruses and might therefore represent a promising option for the complementary treatment of COVID-19 patients. The application of turmeric root in herbal medicine has a very long history. Its bioactive ingredient curcumin shows a broad-spectrum antimicrobial activity. In the present study, we investigated the antiviral activity of aqueous turmeric root extract, the dissolved content of a curcumin-containing nutritional supplement capsule, and pure curcumin against SARS-CoV-2. Turmeric root extract, dissolved turmeric capsule content, and pure curcumin effectively neutralized SARS-CoV-2 at subtoxic concentrations in Vero E6 and human Calu-3 cells. Furthermore, curcumin treatment significantly reduced SARS-CoV-2 RNA levels in cell culture supernatants. Our data uncover curcumin as a promising compound for complementary COVID-19 treatment. Curcumin concentrations contained in turmeric root or capsules used as nutritional supplements completely neutralized SARS-CoV-2 in vitro. Our data argue in favor of appropriate and carefully monitored clinical studies that vigorously test the effectiveness of complementary treatment of COVID-19 patients with curcumin-containing products.


Subject(s)
COVID-19/drug therapy , Curcumin/therapeutic use , SARS-CoV-2/drug effects , Animals , Antiviral Agents/therapeutic use , Cell Line , Chlorocebus aethiops , Curcuma/metabolism , Curcumin/metabolism , Dietary Supplements , Humans , Medicine, Traditional/methods , Plant Extracts/metabolism , Plant Extracts/therapeutic use , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Vero Cells
3.
J Mol Model ; 27(8): 221, 2021 Jul 08.
Article in English | MEDLINE | ID: covidwho-1300483

ABSTRACT

Natural products have served human life as medications for centuries. During the outbreak of COVID-19, a number of naturally derived compounds and extracts have been tested or used as potential remedies against COVID-19. Tetradenia riparia extract is one of the plant extracts that have been deployed and claimed to manage and control COVID-19 by some communities in Tanzania and other African countries. The active compounds isolated from T. riparia are known to possess various biological properties including antimalarial and antiviral. However, the underlying mechanism of the active compounds against SARS-CoV-2 remains unknown. Results in the present work have been interpreted from the view point of computational methods including molecular dynamics, free energy methods, and metadynamics to establish the related mechanism of action. Among the constituents of T. riparia studied, luteolin inhibited viral cell entry and was thermodynamically stable. The title compound exhibit residence time and unbinding kinetics of 68.86 ms and 0.014 /ms, respectively. The findings suggest that luteolin could be potent blocker of SARS-CoV-2 cell entry. The study shades lights towards identification of bioactive constituents from T. riparia against COVID-19, and thus bioassay can be carried out to further validate such observations.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Luteolin/pharmacology , Molecular Dynamics Simulation , Plant Extracts/pharmacology , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/isolation & purification , Antiviral Agents/metabolism , Binding Sites , COVID-19/virology , Host-Pathogen Interactions , Humans , Kinetics , Lamiaceae/chemistry , Luteolin/isolation & purification , Luteolin/metabolism , Plant Extracts/isolation & purification , Plant Extracts/metabolism , Protein Binding , Protein Conformation , Receptors, Virus/metabolism , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism
4.
Molecules ; 26(13)2021 Jul 05.
Article in English | MEDLINE | ID: covidwho-1295889

ABSTRACT

COVID-19 is a pandemic disease caused by the SARS-CoV-2 virus, which is potentially fatal for vulnerable individuals. Disease management represents a challenge for many countries, given the shortage of medicines and hospital resources. The objective of this work was to review the medicinal plants, foods and natural products showing scientific evidence for host protection against various types of coronaviruses, with a focus on SARS-CoV-2. Natural products that mitigate the symptoms caused by various coronaviruses are also presented. Particular attention was placed on natural products that stabilize the Renin-Angiotensin-Aldosterone System (RAAS), which has been associated with the entry of the SARS-CoV-2 into human cells.


Subject(s)
Biological Products/pharmacology , Coronavirus/drug effects , Phytotherapy/methods , Plant Extracts/pharmacology , SARS-CoV-2/drug effects , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Biological Products/metabolism , COVID-19/drug therapy , COVID-19/virology , Humans , Pandemics , Plant Extracts/metabolism , Plants/chemistry , Renin-Angiotensin System/drug effects
5.
PLoS One ; 16(6): e0248479, 2021.
Article in English | MEDLINE | ID: covidwho-1266543

ABSTRACT

The Coronavirus disease (COVID-19) caused by the virus SARS-CoV-2 has become a global pandemic in a very short time span. Currently, there is no specific treatment or vaccine to counter this highly contagious disease. There is an urgent need to find a specific cure for the disease and global efforts are directed at developing SARS-CoV-2 specific antivirals and immunomodulators. Ayurvedic Rasayana therapy has been traditionally used in India for its immunomodulatory and adaptogenic effects, and more recently has been included as therapeutic adjuvant for several maladies. Amongst several others, Withania somnifera (Ashwagandha), Tinospora cordifolia (Guduchi) and Asparagus racemosus (Shatavari) play an important role in Rasayana therapy. The objective of this study was to explore the immunomodulatory and anti SARS-CoV2 potential of phytoconstituents from Ashwagandha, Guduchi and Shatavari using network pharmacology and docking. The plant extracts were prepared as per ayurvedic procedures and a total of 31 phytoconstituents were identified using UHPLC-PDA and mass spectrometry studies. To assess the immunomodulatory potential of these phytoconstituents an in-silico network pharmacology model was constructed. The model predicts that the phytoconstituents possess the potential to modulate several targets in immune pathways potentially providing a protective role. To explore if these phytoconstituents also possess antiviral activity, docking was performed with the Spike protein, Main Protease and RNA dependent RNA polymerase of the virus. Interestingly, several phytoconstituents are predicted to possess good affinity for the three targets, suggesting their application for the termination of viral life cycle. Further, predictive tools indicate that there would not be adverse herb-drug pharmacokinetic-pharmacodynamic interactions with concomitantly administered drug therapy. We thus make a compelling case to evaluate the potential of these Rasayana botanicals as therapeutic adjuvants in the management of COVID-19 following rigorous experimental validation.


Subject(s)
Antiviral Agents/metabolism , Asparagus Plant/chemistry , COVID-19/metabolism , Immunologic Factors/metabolism , Molecular Docking Simulation/methods , Plant Extracts/metabolism , SARS-CoV-2/enzymology , Tinospora/chemistry , Withania/chemistry , Antiviral Agents/pharmacokinetics , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Coronavirus 3C Proteases/metabolism , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Herb-Drug Interactions , Humans , Immunologic Factors/pharmacokinetics , India , Medicine, Ayurvedic/methods , Phytotherapy/methods , Plant Extracts/pharmacokinetics , Protein Binding , Spike Glycoprotein, Coronavirus/metabolism
6.
Viruses ; 13(5)2021 05 02.
Article in English | MEDLINE | ID: covidwho-1224250

ABSTRACT

In late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic emerged to severely impact the global population, creating an unprecedented need for effective treatments. This study aims to investigate the potential of Scutellaria barbata D. Don (SB) as a treatment for SARS-CoV-2 infection through the inhibition of the proteases playing important functions in the infection by SARS-CoV-2. FRET assay was applied to investigate the inhibitory effects of SB on the two proteases involved in SARS-CoV-2 infection, Mpro and TMPRSS2. Additionally, to measure the potential effectiveness of SB treatment on infection inhibition, cellular models based on the Calu3 and VeroE6 cells and their TMPRSS2- expressing derivatives were assessed by viral pseudoparticles (Vpp) infection assays. The experimental approaches were conjugated with LC/MS analyses of the aqueous extracts of SB to identify the major constituent compounds, followed by a literature review to determine the potential active components of the inhibitory effects on protease activities. Our results showed that SB extracts inhibited the enzyme activities of Mpro and TMPRSS2. Furthermore, SB extracts effectively inhibited SARS-CoV-2 Vpp infection through a TMPRSS2-dependent mechanism. The aqueous extract analysis identified six major constituent compounds present in SB. Some of them have been known associated with inhibitory activities of TMPRSS2 or Mpro. Thus, SB may effectively prevent SARS-CoV-2 infection and replication through inhibiting Mpro and TMPRSS2 protease activities.


Subject(s)
COVID-19/drug therapy , Coronavirus 3C Proteases/metabolism , Plant Extracts/pharmacology , Serine Endopeptidases/metabolism , Animals , COVID-19/metabolism , Cell Line , Chlorocebus aethiops , Coronavirus 3C Proteases/drug effects , Humans , Lung/virology , Pandemics , Peptide Hydrolases , Peptidyl-Dipeptidase A/metabolism , Plant Extracts/metabolism , Proteolysis , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Scutellaria , Serine Endopeptidases/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
7.
Mol Divers ; 25(3): 1963-1977, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1184693

ABSTRACT

The Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus, SARS-CoV-2, has recently emerged as a pandemic. Here, an attempt has been made through in-silico high throughput screening to explore the antiviral compounds from traditionally used plants for antiviral treatments in India namely, Tea, Neem and Turmeric, as potential inhibitors of two widely studied viral proteases, main protease (Mpro) and papain-like protease (PLpro) of the SARS-CoV-2. Molecular docking study using BIOVIA Discovery Studio 2018 revealed, (-)-epicatechin-3-O-gallate (ECG), a tea polyphenol has a binding affinity toward both the selected receptors, with the lowest CDocker energy - 46.22 kcal mol-1 for SARS-CoV-2 Mpro and CDocker energy - 44.72 kcal mol-1 for SARS-CoV-2 PLpro, respectively. The SARS-CoV-2 Mpro complexed with (-)-epicatechin-3-O-gallate, which had shown the best binding affinity was subjected to molecular dynamics simulations to validate its binding affinity, during which, the root-mean-square-deviation values of SARS-CoV-2 Mpro-Co-crystal ligand (N3) and SARS-CoV-2 Mpro- (-)-epicatechin-3-O-gallate systems were found to be more stable than SARS-CoV-2 Mpro system. Further, (-)-epicatechin-3-O-gallate was subjected to QSAR analysis which predicted IC50 of 0.3281 nM against SARS-CoV-2 Mpro. Overall, (-)-epicatechin-3-O-gallate showed a potential binding affinity with SARS-CoV-2 Mpro and could be proposed as a potential natural compound for COVID-19 treatment.


Subject(s)
Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Molecular Dynamics Simulation , Plant Extracts/pharmacology , Protease Inhibitors/pharmacology , SARS-CoV-2/enzymology , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Coronavirus Papain-Like Proteases/chemistry , Coronavirus Papain-Like Proteases/metabolism , Plant Extracts/chemistry , Plant Extracts/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Protein Binding , Protein Conformation , SARS-CoV-2/drug effects , Thermodynamics
8.
Vascul Pharmacol ; 138: 106856, 2021 06.
Article in English | MEDLINE | ID: covidwho-1144979

ABSTRACT

COVID-19, a global-pandemic binds human-lung-ACE2. ACE2 causes vasodilatation. ACE2 works in balance with ACE1. The vaso-status maintains blood-pressure/vascular-health which is demolished in Covid-19 manifesting aldosterone/salt-deregulations/inflammations/endothelial-dysfunctions/hyper-hypo- tension, sepsis/hypovolemic-shock and vessel-thrombosis/coagulations. Here, nigellidine, an indazole-alkaloid was analyzed by molecular-docking for binding to different Angiotensin-binding-proteins (enzymes, ACE1(6en5)/ACE2(4aph)/receptors, AT1(6os1)/AT2(5xjm)) and COVID-19 spike-glycoprotein(6vsb). Nigellidine strongly binds to the spike-protein at the hinge-region/active-site-opening which may hamper proper-binding of nCoV2-ACE2 surface. Nigellidine effectively binds in the Angiotensin- II binding-site/entry-pocket (-7.54 kcal/mol, -211.76, Atomic-Contact-Energy; ACE-value) of ACE2 (Ki 8.68 and 8.3 µmol) in comparison to known-binder EGCG (-4.53) and Theaflavin-di-gallate (-2.85). Nigellidine showed strong-binding (Ki, 50.93 µmol/binding-energy -5.48 kcal/mol) to mono/multi-meric ACE1. Moreover, it binds Angiotensin-receptors, AT1/AT2 (Ki, 42.79/14.22 µmol, binding-energy, -5.96/-6.61 kcal/mol) at active-sites, respectively. This article reports the novel binding of nigellidine and subsequent blockage of angiotensin-binding proteins. The ACEs-blocking could restore Angiotensin-level, restrict vaso-turbulence in Covid patients and receptor-blocking might stop inflammatory/vascular impairment. Nigellidine may slowdown the vaso-fluctuations due to Angiotensin-deregulations in Covid patients. Angiotensin II-ACE2 binding (ACE-value -294.81) is more favorable than nigellidine-ACE2. Conversely, nigellidine-ACE1 binding-energy/Ki is lower than nigellidine-ACE2 values indicating a balanced-state between constriction-dilatation. Moreover, nigellidine binds to the viral-spike, closer-proximity to its ACE2 binding-domain. Taken together, Covid patients/elderly-patients, comorbid-patients (with hypertensive/diabetic/cardiac/renal-impairment, counting >80% of non-survivors) could be greatly benefited.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Nigella sativa , Peptidyl-Dipeptidase A/metabolism , Plant Extracts/metabolism , Receptor, Angiotensin, Type 1/metabolism , Receptor, Angiotensin, Type 2/metabolism , Angiotensin-Converting Enzyme 2/chemistry , COVID-19/pathology , COVID-19/prevention & control , Comorbidity , Computer Simulation/trends , Drug Evaluation, Preclinical/methods , Humans , Molecular Docking Simulation/methods , Peptidyl-Dipeptidase A/chemistry , Plant Extracts/isolation & purification , Plant Extracts/therapeutic use , Protein Binding/physiology , Protein Structure, Secondary , Protein Structure, Tertiary , Receptor, Angiotensin, Type 1/chemistry , Receptor, Angiotensin, Type 2/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism
9.
J Food Biochem ; 45(1): e13557, 2021 01.
Article in English | MEDLINE | ID: covidwho-917749

ABSTRACT

SARS-CoV-2 (previously 2019-nCoV), the pathogenic agent of COVID-19 disease, started to expand from Wuhan, China, on December 2019 and in 2 months, it spread worldwide giving origin to a pandemic. COVID-19 has a stronger transmission capacity by inhalation of infectious aerosols and after an incubation time of 3-14 days, it may be responsible for diseases ranging from the asymptomatic to fatal consequences. COVID-19 has emerged as a multifaceted, multisystem, multi-organ disorder, which produces its pathogenic effects through a quite ubiquitous target at the level of multiple organs and in which oxidative stress and inflammatory process play relevant roles. Thus, besides the development of a pharmacological therapy, in the field of alternative and coadjutant therapeutic, the use of dietary supplements or nutraceuticals for the prevention or treatment of SARS-CoV-2 infection may be a useful strategy. Herein, we specifically comment on some literature evidences, which link the food-derived antioxidants and metal-chelating agents with treatment and prevention of oxidative stress and inflammation that play a key role in the progression of COVID-19. PRACTICAL APPLICATIONS: Oxidative stress and inflammation are key factors increasing COVID-19 severity especially in the presence of chronic diseases associated with the antioxidant system fragility. These evidences support the recommendation of antioxidants supplementation as useful strategies against COVID-19. In light with these observations, herein, a comment which describes the major antioxidants and metal-chelating agents from food sources that might be useful for the treatment and prevention of oxidative stress and inflammation during COVID-19.


Subject(s)
Antioxidants/metabolism , COVID-19/diet therapy , Plant Extracts/metabolism , COVID-19/metabolism , COVID-19/virology , Chelating Agents/metabolism , Dietary Supplements/analysis , Food Analysis , Humans , Oxidative Stress , SARS-CoV-2/physiology
10.
Phytother Res ; 35(2): 908-919, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-777655

ABSTRACT

COVID-19 pandemic is currently decimating the world's most advanced technologies and largest economies and making its way to the continent of Africa. Weak medical infrastructure and over-reliance on medical aids may eventually predict worse outcomes in Africa. To reverse this trend, Africa must re-evaluate the only area with strategic advantage; phytotherapy. One of the many plants with previous antiviral potency is against RNA viruses is Aframomum melegueta. In this study, one hundred (100) A. melegueta secondary metabolites have been mined and computational evaluated for inhibition of host furin, and SARS-COV-2 targets including 3C-like proteinase (Mpro /3CLpro ), 2'-O-ribose methyltransferase (nsp16) and surface glycoprotein/ACE2 receptor interface. Silica-gel column partitioning of A. melegueta fruit/seed resulted in 6 fractions tested against furin activity. Diarylheptanoid (Letestuianin A), phenylpropanoid (4-Cinnamoyl-3-hydroxy-spiro[furan-5,2'-(1'H)-indene]-1',2,3'(2'H,5H)-trione), flavonoids (Quercetin, Apigenin and Tectochrysin) have been identified as high-binding compounds to SARS-COV-2 targets in a polypharmacology manner. Di-ethyl-ether (IC50 = 0.03 mg/L), acetone (IC50 = 1.564 mg/L), ethyl-acetate (IC50 = 0.382 mg/L) and methanol (IC50 = 0.438 mg/L) fractions demonstrated the best inhibition in kinetic assay while DEF, ASF and MEF completely inhibited furin-recognition sequence containing Ebola virus-pre-glycoprotein. In conclusion, A. melegueta and its secondary metabolites have potential for addressing the therapeutic needs of African population during the COVID-19 pandemic.


Subject(s)
COVID-19/drug therapy , Furin/antagonists & inhibitors , Phytotherapy/methods , Plant Extracts/therapeutic use , SARS-CoV-2/drug effects , Zingiberaceae/chemistry , COVID-19/epidemiology , Drug Evaluation, Preclinical/methods , Fruit/chemistry , Fruit/metabolism , Furin/metabolism , Humans , In Vitro Techniques , Metabolome/physiology , Molecular Docking Simulation , Pandemics , Plant Extracts/chemistry , Plant Extracts/metabolism , Polypharmacology , SARS-CoV-2/pathogenicity , Seeds/chemistry , Seeds/metabolism , Zingiberaceae/metabolism
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