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1.
J Mol Model ; 27(11): 341, 2021 Nov 03.
Article in English | MEDLINE | ID: covidwho-1499466

ABSTRACT

From the beginning of pandemic, more than 240 million people have been infected with a death rate higher than 2%. Indeed, the current exit strategy involving the spreading of vaccines must be combined with progress in effective treatment development. This scenario is sadly supported by the vaccine's immune activation time and the inequalities in the global immunization schedule. Bringing the crises under control means providing the world population with accessible and impactful new therapeutics. We screened a natural product library that contains a unique collection of 2370 natural products into the binding site of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). According to the docking score and to the interaction at the active site, three phenylethanoid glycosides (forsythiaside A, isoacteoside, and verbascoside) were selected. In order to provide better insight into the atomistic interaction and test the impact of the three selected compounds at the binding site, we resorted to a half microsecond-long molecular dynamics simulation. As a result, we are showing that forsythiaside A is the most stable molecule and it is likely to possess the highest inhibitory effect against SARS-CoV-2 Mpro. Phenylethanoid glycosides also have been reported to have both protease and kinase activity. This kinase inhibitory activity is very beneficial in fighting viruses inside the body as kinases are required for viral entry, metabolism, and/or reproduction. The dual activity (kinase/protease) of phenylethanoid glycosides makes them very promising anit-COVID-19 agents.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus Protease Inhibitors/pharmacology , Glycosides/pharmacology , Antiviral Agents/chemistry , Binding Sites , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Coronavirus Protease Inhibitors/chemistry , Drug Evaluation, Preclinical , Glucosides/chemistry , Glucosides/metabolism , Glucosides/pharmacology , Glycosides/chemistry , Glycosides/metabolism , Hydrogen Bonding , Molecular Docking Simulation , Molecular Dynamics Simulation , Phenols/chemistry , Phenols/metabolism , Phenols/pharmacology
2.
Biomolecules ; 11(11)2021 10 27.
Article in English | MEDLINE | ID: covidwho-1488476

ABSTRACT

Glycosylation is an important post-translational modification that affects a wide variety of physiological functions. DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) is a protein expressed in antigen-presenting cells that recognizes a variety of glycan epitopes. Until now, the binding of DC-SIGN to SARS-CoV-2 Spike glycoprotein has been reported in various articles and is regarded to be a factor in systemic infection and cytokine storm. The mechanism of DC-SIGN recognition offers an alternative method for discovering new medication for COVID-19 treatment. Here, we discovered three potential pockets that hold different glycan epitopes by performing molecular dynamics simulations of previously reported oligosaccharides. The "EPN" motif, "NDD" motif, and Glu354 form the most critical pocket, which is known as the Core site. We proposed that the type of glycan epitopes, rather than the precise amino acid sequence, determines the recognition. Furthermore, we deduced that oligosaccharides could occupy an additional site, which adds to their higher affinity than monosaccharides. Based on our findings and previously described glycoforms on the SARS-CoV-2 Spike, we predicted the potential glycan epitopes for DC-SIGN. It suggested that glycan epitopes could be recognized at multiple sites, not just Asn234, Asn149 and Asn343. Subsequently, we found that Saikosaponin A and Liquiritin, two plant glycosides, were promising DC-SIGN antagonists in silico.


Subject(s)
COVID-19/immunology , Cell Adhesion Molecules/antagonists & inhibitors , Epitopes/chemistry , Glycosides/chemistry , Lectins, C-Type/antagonists & inhibitors , Polysaccharides/chemistry , Receptors, Cell Surface/antagonists & inhibitors , Amino Acid Motifs , Binding Sites , COVID-19/metabolism , Computer Simulation , Cytokines/metabolism , Flavanones/chemistry , Glucosides/chemistry , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Monosaccharides/chemistry , Oleanolic Acid/analogs & derivatives , Oleanolic Acid/chemistry , Saponins/chemistry , Spike Glycoprotein, Coronavirus/chemistry
3.
Molecules ; 26(19)2021 Oct 07.
Article in English | MEDLINE | ID: covidwho-1463771

ABSTRACT

3CL-Pro is the SARS-CoV-2 main protease (MPro). It acts as a homodimer to cleave the large polyprotein 1ab transcript into proteins that are necessary for viral growth and replication. 3CL-Pro has been one of the most studied SARS-CoV-2 proteins and a main target of therapeutics. A number of drug candidates have been reported, including natural products. Here, we employ elaborate computational methods to explore the dimerization of the 3CL-Pro protein, and we formulate a computational context to identify potential inhibitors of this process. We report that fortunellin (acacetin 7-O-neohesperidoside), a natural flavonoid O-glycoside, and its structural analogs are potent inhibitors of 3CL-Pro dimerization, inhibiting viral plaque formation in vitro. We thus propose a novel basis for the search of pharmaceuticals as well as dietary supplements in the fight against SARS-CoV-2 and COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Flavonoids/pharmacology , Glycosides/pharmacology , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemistry , Chlorocebus aethiops , Coronavirus 3C Proteases/metabolism , Flavonoids/chemistry , Glycosides/chemistry , Humans , Molecular Docking Simulation , Polyphenols/chemistry , Polyphenols/pharmacology , Protease Inhibitors/chemistry , Protein Multimerization/drug effects , SARS-CoV-2/metabolism , Vero Cells
4.
J Ethnopharmacol ; 279: 114356, 2021 Oct 28.
Article in English | MEDLINE | ID: covidwho-1274322

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Herbacetin is an active constituent of traditional Chinese medicines such as Ephedra sinica Stapf (MaHuang) and Sedum roseum (L.). Scop. (Hong JingTian). MaHuang was used to treat cough, asthma, fever, and edema for more than 5000 years, while Hong JingTian was used to treat depression, fatigue, cancers, and cardiovascular disease. Recent studies indicate that herbacetin and its glycosides play a critical role in the pharmacological activities of these herbs. However, currently, no comprehensive review on herbacetin has been published yet. AIM OF THE STUDY: This review aimed to summarize information on the chemistry, natural sources, and pharmacokinetic features of herbacetin, with an emphasis on its pharmacological activities and possible mechanisms of action. MATERIALS AND METHODS: A literature search was performed on the Web of Science, PubMed, and China Knowledge Resource Integrated databases (CNKI) using the search term "herbacetin" ("all fields") from 1935 to 2020. Information was also obtained from classic books of Chinese herbal medicine, Chinese pharmacopeia, and the database "The Plant List" (www.theplantlist.org). Studies have been analyzed and summarized in this review if they dealt with chemistry, taxonomy, pharmacokinetic, and pharmacological activity. RESULTS: Herbacetin is distributed in various plants and can be extracted or synthesized. It showed diverse pharmacological activities including antioxidant, antiviral, anti-inflammatory, anticancer, antidiabetic, and anticholinesterase. It is thought to have great potential in cancer treatment, especially colon and skin cancers. However, the bioavailability of herbacetin is low and the toxicity of herbacetin has not been studied. Thus, more studies are required to solve these problems. CONCLUSIONS: Herbacetin shows promising pharmacological activities against multiple diseases. Future research should focus on improving bioavailability, further studying its pharmacological mechanism, evaluating its toxicity and optimal dose, and performing the clinical assessment. We hope that the present review will serve as a guideline for future research on herbacetin.


Subject(s)
Drugs, Chinese Herbal/pharmacology , Flavonoids/pharmacology , Medicine, Chinese Traditional/methods , Animals , Drugs, Chinese Herbal/chemistry , Ethnopharmacology , Flavonoids/isolation & purification , Glycosides/chemistry , Glycosides/isolation & purification , Glycosides/pharmacology , Humans
5.
Int J Mol Sci ; 22(8)2021 Apr 09.
Article in English | MEDLINE | ID: covidwho-1298159

ABSTRACT

A comparative phytochemical study on the phenylethanoid glycoside (PhEG) composition of the underground organs of three Plantago species (P. lanceolata, P. major, and P. media) and that of the fruit wall and seed parts of Forsythia suspensa and F. europaea fruits was performed. The leaves of these Forsythia species and six cultivars of the hybrid F. × intermedia were also analyzed, demonstrating the tissue-specific accumulation and decomposition of PhEGs. Our analyses confirmed the significance of selected tissues as new and abundant sources of these valuable natural compounds. The optimized heat treatment of tissues containing high amounts of the PhEG plantamajoside (PM) or forsythoside A (FA), which was performed in distilled water, resulted in their characteristic isomerizations. In addition to PM and FA, high amounts of the isomerization products could also be isolated after heat treatment. The isomerization mechanisms were elucidated by molecular modeling, and the structures of PhEGs were identified by nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry (HR-MS) techniques, also confirming the possibility of discriminating regioisomeric PhEGs by tandem MS. The PhEGs showed no cytostatic activity in non-human primate Vero E6 cells, supporting their safe use as natural medicines and allowing their antiviral potency to be tested.


Subject(s)
Forsythia/chemistry , Glycosides/chemistry , Phytochemicals/chemistry , Plantago/chemistry , Animals , Chlorocebus aethiops , Chromatography, High Pressure Liquid , Forsythia/metabolism , Glycosides/metabolism , Glycosides/pharmacology , Isomerism , Molecular Conformation , Molecular Structure , Organ Specificity , Phytochemicals/metabolism , Phytochemicals/pharmacology , Plant Extracts/chemistry , Plant Extracts/pharmacology , Plantago/metabolism , Structure-Activity Relationship , Vero Cells
6.
Life Sci ; 277: 119508, 2021 Jul 15.
Article in English | MEDLINE | ID: covidwho-1185152

ABSTRACT

Antiviral strategies for viruses that utilize proteoglycan core proteins (syndecans and glypicans) as receptors should focus on heparan sulfate (HS) biosynthesis rather than on inhibition of these sugar chains. Here, we show that heparin and certain xylosides, which exhibit in vitro viral entry inhibitory properties against HSV-1, HSV-2, HPV-16, HPV-31, HVB, HVC, HIV-1, HTLV-1, SARS-CoV-2, HCMV, DENV-1, and DENV-2, stimulated HS biosynthesis at the cell surface 2- to 3-fold for heparin and up to 10-fold for such xylosides. This is consistent with the hypothesis from a previous study that for core protein attachment, viruses are glycosylated at HS attachment sites (i.e., serine residues intended to receive the D-xylose molecule for initiating HS chains). Heparanase overexpression, endocytic entry, and syndecan shedding enhancement, all of which are observed during viral infection, lead to glycocalyx deregulation and appear to be direct consequences of this hypothesis. In addition to the appearance of type 2 diabetes and the degradation of HS observed during viral infection, we linked this hypothesis to that proposed in a previous publication.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Biosynthetic Pathways/drug effects , Heparitin Sulfate/metabolism , Virus Internalization/drug effects , Animals , Drug Discovery , Glycosides/chemistry , Glycosides/pharmacology , Heparin/chemistry , Heparin/pharmacology , Humans , Virus Diseases/drug therapy
7.
Int J Nanomedicine ; 16: 1789-1804, 2021.
Article in English | MEDLINE | ID: covidwho-1124835

ABSTRACT

BACKGROUND: SARS-COVID-2 has recently been one of the most life-threatening problems which urgently needs new therapeutic antiviral agents, especially those of herbal origin. PURPOSE: The study aimed to load acaciin (ACA) into the new self-assembled nanofibers (NFs) followed by investigating their possible antiviral effect against bovine coronavirus (BCV) as a surrogate model for SARS-COV-2. METHODS: ACA was identified using 1H-NMR and DEPT-Q 13C-NMR spectroscopy, the molecular docking study was performed using Autodock 4 and a modification of the traditional solvent injection method was applied for the synthesis of the biodegradable NFs. Different characterization techniques were used to inspect the formation of the NFs, which is followed by antiviral investigation against BCV as well as MTT assay using MDBK cells. RESULTS: Core/shell NFs, ranging between 80-330 nm with tiny thorn-like branches, were formed which attained an enhanced encapsulation efficiency (97.5 ± 0.53%, P<0.05) and a dual controlled release (a burst release of 65% at 1 h and a sustained release up to >24 h). The antiviral investigation of the formed NFs revealed a significant inhibition of 98.88 ± 0.16% (P<0.05) with IC50 of 12.6 µM against BCV cells. CONCLUSION: The results introduced a new, time/cost-saving strategy for the synthesis of biodegradable NFs without the need for electric current or hazardous cross-linking agents. Moreover, it provided an innovative avenue for the discovery of drugs of herbal origin for the fight against SARS-CoV-2 infection.


Subject(s)
Coronavirus, Bovine/drug effects , Glycosides/pharmacology , Nanofibers/chemistry , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/virology , Cell Line , Glycosides/chemistry , Glycosides/isolation & purification , Glycosides/therapeutic use , Humans , Ligands , Models, Biological , Molecular Docking Simulation , Nanofibers/ultrastructure , Solvents , Ultraviolet Rays
8.
Viruses ; 13(2)2021 02 15.
Article in English | MEDLINE | ID: covidwho-1122257

ABSTRACT

Coronavirus disease-19 (COVID-19) pandemic, caused by the novel SARS-CoV-2 virus, continues to be a global threat. The number of cases and deaths will remain escalating due to the lack of effective therapeutic agents. Several studies have established the importance of the viral main protease (Mpro) in the replication of SARS-CoV-2 which makes it an attractive target for antiviral drug development, including pharmaceutical repurposing and other medicinal chemistry approaches. Identification of natural products with considerable inhibitory potential against SARS-CoV-2 could be beneficial as a rapid and potent alternative with drug-likeness by comparison to de novo antiviral drug discovery approaches. Thereof, we carried out the structure-based screening of natural products from Echinacea-angustifolia, commonly used to prevent cold and other microbial respiratory infections, targeting SARS-CoV-2 Mpro. Four natural products namely, Echinacoside, Quercetagetin 7-glucoside, Levan N, Inulin from chicory, and 1,3-Dicaffeoylquinic acid, revealed significant docking energy (>-10 kcal/mol) in the SARS-CoV-2 Mpro catalytic pocket via substantial intermolecular contacts formation against co-crystallized ligand (<-4 kcal/mol). Furthermore, the docked poses of SARS-CoV-2 Mpro with selected natural products showed conformational stability through molecular dynamics. Exploring the end-point net binding energy exhibited substantial contribution of Coulomb and van der Waals interactions to the stability of respective docked conformations. These results advocated the natural products from Echinacea angustifolia for further experimental studies with an elevated probability to discover the potent SARS-CoV-2 Mpro antagonist with higher affinity and drug-likeness.


Subject(s)
Antiviral Agents/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Echinacea/chemistry , Protease Inhibitors/chemistry , Binding Sites , Drug Discovery , Flavones/chemistry , Fructans/chemistry , Glycosides/chemistry , Inulin/chemistry , Molecular Docking Simulation , Phytochemicals/chemistry , Protein Binding , Quinic Acid/analogs & derivatives , Quinic Acid/chemistry
9.
Viruses ; 13(2)2021 02 15.
Article in English | MEDLINE | ID: covidwho-1085037

ABSTRACT

Coronavirus disease-19 (COVID-19) pandemic, caused by the novel SARS-CoV-2 virus, continues to be a global threat. The number of cases and deaths will remain escalating due to the lack of effective therapeutic agents. Several studies have established the importance of the viral main protease (Mpro) in the replication of SARS-CoV-2 which makes it an attractive target for antiviral drug development, including pharmaceutical repurposing and other medicinal chemistry approaches. Identification of natural products with considerable inhibitory potential against SARS-CoV-2 could be beneficial as a rapid and potent alternative with drug-likeness by comparison to de novo antiviral drug discovery approaches. Thereof, we carried out the structure-based screening of natural products from Echinacea-angustifolia, commonly used to prevent cold and other microbial respiratory infections, targeting SARS-CoV-2 Mpro. Four natural products namely, Echinacoside, Quercetagetin 7-glucoside, Levan N, Inulin from chicory, and 1,3-Dicaffeoylquinic acid, revealed significant docking energy (>-10 kcal/mol) in the SARS-CoV-2 Mpro catalytic pocket via substantial intermolecular contacts formation against co-crystallized ligand (<-4 kcal/mol). Furthermore, the docked poses of SARS-CoV-2 Mpro with selected natural products showed conformational stability through molecular dynamics. Exploring the end-point net binding energy exhibited substantial contribution of Coulomb and van der Waals interactions to the stability of respective docked conformations. These results advocated the natural products from Echinacea angustifolia for further experimental studies with an elevated probability to discover the potent SARS-CoV-2 Mpro antagonist with higher affinity and drug-likeness.


Subject(s)
Antiviral Agents/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Echinacea/chemistry , Protease Inhibitors/chemistry , Binding Sites , Drug Discovery , Flavones/chemistry , Fructans/chemistry , Glycosides/chemistry , Inulin/chemistry , Molecular Docking Simulation , Phytochemicals/chemistry , Protein Binding , Quinic Acid/analogs & derivatives , Quinic Acid/chemistry
10.
Comb Chem High Throughput Screen ; 24(10): 1795-1802, 2021.
Article in English | MEDLINE | ID: covidwho-918979

ABSTRACT

BACKGROUND: SARS-CoV-2 has been shown to bind the host cell ACE2 receptor through its spike protein receptor binding domain (RBD), required for its entry into the host cells. OBJECTIVE: We have screened phytocompounds from a medicinal herb, Tinospora cordifolia for their capacities to interrupt the viral RBD and host ACE2 interactions. METHODS: We employed molecular docking to screen phytocompounds in T. cordifolia against the ACE2-RBD complex, performed molecular dynamics (MD) simulation, and estimated the electrostatic component of binding free energy. RESULTS: 'Tinocordiside' docked very well at the center of the interface of ACE2-RBD complex, and was found to be well stabilized during MD simulation. Tinocordiside incorporation significantly decreased the electrostatic component of binding free energies of the ACE2-RBD complex (23.5 and 17.10 kcal/mol in the trajectories without or with the ligand, respectively). As the basal rate constant of protein association is in the order of 5 (105 to 106 M-1S-1), there might be no big conformational change or loop reorganization, but involves only local conformational change typically observed in the diffusion-controlled association. Taken together, the increase in global flexibility of the complex clearly indicates the start of unbinding process of the complex. CONCLUSION: It indicates that such an interruption of electrostatic interactions between the RBD and ACE2, and the increase in global flexibility of the complex would weaken or block SARSCoV- 2 entry and its subsequent infectivity. We postulate that natural phytochemicals like Tinocordiside could be viable options for controlling SARS-CoV-2 contagion and its entry into host cells.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/pharmacology , Glycosides/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Tinospora/chemistry , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Gene Expression , Glycosides/chemistry , Glycosides/isolation & purification , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Kinetics , Molecular Docking Simulation , Molecular Dynamics Simulation , Plant Extracts/chemistry , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Static Electricity , Thermodynamics , Virus Internalization/drug effects
11.
Steroids ; 165: 108759, 2021 01.
Article in English | MEDLINE | ID: covidwho-917434

ABSTRACT

Gastric ulcers are a very common public health problem affecting up to 10% worldwide. Russelioside B is a steroidal glycoside isolated from several Caralluma species. No study tested the ulcer healing potential of the compound. The current study aimed to assess the protective effect of russelioside B against ethanol-induced gastric mucosal injury in rats. Ulcer was induced on rats by a single intragastric dose of absolute ethanol (5 mL/kg). Rats were randomly assorted into four groups (n = 8) and given treatments (Antodine, 20 mg/kg or russelioside B, 50 mg/kg) by oral gavage 1 h before ulcer induction. Pretreatment with russelioside B (50 mg/kg) attenuated the gastric mucosal injury as proved by a decrease of ulcer index, and histological scores. It suppressed the gastric inflammation by a significant lowering the tumor necrosis factor-α and interleukin-6 levels with myeloperoxidase activity (which are also aggravating factors in the case of Covid-19 infection). In addition, administration of russelioside B halted the gastric oxidative stress via inhibition of lipid peroxides by maintaining reduced glutathione and by decreasing malondialdehyde. It was able also to restore the sharp drop in the levels of heat shock protein-70, vascular endothelial growth factor and prostaglandin E2 induced by ethanol. Additionally, it showed carbonic anhydrase inhibition activity. The gastroprotective action of russelioside B was umpired through multi mechanistic actions; suppression of gastric oxidative stress, inflammation, anti-apoptotic activities and enhanced gastric mucosal protection by up-regulation of endothelial growth factor, normalization of heat shock protein-70 and prostaglandin E2. These actions were comparable in part to some classical antiulcer drugs such as Antodine.


Subject(s)
Dinoprostone/genetics , Glycosides/pharmacology , HSP70 Heat-Shock Proteins/genetics , Pregnanes/pharmacology , Stomach Ulcer/drug therapy , Animals , Anti-Ulcer Agents/pharmacology , Apocynaceae/chemistry , COVID-19/drug therapy , COVID-19/genetics , COVID-19/virology , Disease Models, Animal , Ethanol/toxicity , Gastric Mucosa/drug effects , Gastric Mucosa/pathology , Gene Expression Regulation/drug effects , Glycosides/chemistry , Humans , Interleukin-6/genetics , Oxidative Stress/drug effects , Peroxidase/genetics , Pregnanes/chemistry , Rats , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Stomach Ulcer/chemically induced , Stomach Ulcer/genetics , Stomach Ulcer/pathology , Tumor Necrosis Factor-alpha/genetics
12.
Int J Biol Macromol ; 161: 936-938, 2020 Oct 15.
Article in English | MEDLINE | ID: covidwho-593423

ABSTRACT

This short report is dedicated to the description of the wide antiviral and antibacterial activity of the immune-modulating agent Panavir®. Panavir® is a high-molecular-weight fraction of the polysaccharides extracted from the shoots of the Solanum tuberosum. It demonstrates activity against many types of viruses, including animal coronavirus and also against bacterial infections. These properties look very promising considering the COVID-19 epidemy and allow propose that Panavir® would be effective in the therapy of the SARS-CoV-2 infection.


Subject(s)
Antiviral Agents/pharmacology , Glycosides/pharmacology , Herpes Genitalis/drug therapy , Adult , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Disease Models, Animal , Dysentery, Bacillary/drug therapy , Female , Glycosides/chemistry , Glycosides/therapeutic use , Humans , Klebsiella Infections/drug therapy , Klebsiella pneumoniae/drug effects , Male , Mice , Middle Aged , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , SARS-CoV-2 , Shigella flexneri/drug effects , Young Adult
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