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1.
Sci Adv ; 8(8): eabi6110, 2022 Feb 25.
Article in English | MEDLINE | ID: covidwho-1714330

ABSTRACT

The spread of SARS-CoV-2 and ongoing COVID-19 pandemic underscores the need for new treatments. Here we report that cannabidiol (CBD) inhibits infection of SARS-CoV-2 in cells and mice. CBD and its metabolite 7-OH-CBD, but not THC or other congeneric cannabinoids tested, potently block SARS-CoV-2 replication in lung epithelial cells. CBD acts after viral entry, inhibiting viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcription. CBD inhibits SARS-CoV-2 replication in part by up-regulating the host IRE1α RNase endoplasmic reticulum (ER) stress response and interferon signaling pathways. In matched groups of human patients from the National COVID Cohort Collaborative, CBD (100 mg/ml oral solution per medical records) had a significant negative association with positive SARS-CoV-2 tests. This study highlights CBD as a potential preventative agent for early-stage SARS-CoV-2 infection and merits future clinical trials. We caution against use of non-medical formulations including edibles, inhalants or topicals as a preventative or treatment therapy at the present time.


Subject(s)
Antiviral Agents/pharmacology , Cannabidiol/pharmacology , Host-Pathogen Interactions/drug effects , Immunity, Innate/drug effects , SARS-CoV-2/drug effects , A549 Cells , Animals , Antiviral Agents/chemistry , COVID-19/drug therapy , COVID-19/virology , Cannabidiol/chemistry , Cannabidiol/metabolism , Chlorocebus aethiops , Endoplasmic Reticulum Stress/drug effects , Endoribonucleases/genetics , Endoribonucleases/metabolism , Epithelial Cells/virology , Female , Gene Expression Regulation, Viral/drug effects , Host-Pathogen Interactions/physiology , Humans , Interferons/metabolism , Mice , /metabolism , SARS-CoV-2/physiology , Vero Cells , Virus Internalization/drug effects , Virus Replication/drug effects
2.
Mar Drugs ; 20(2)2022 Feb 17.
Article in English | MEDLINE | ID: covidwho-1708635

ABSTRACT

Omicron is an emerging SARS-CoV-2 variant, evolved from the Indian delta variant B.1.617.2, which is currently infecting worldwide. The spike glycoprotein, an important molecule in the pathogenesis and transmissions of SARS-CoV-2 variants, especially omicron B.1.1.529, shows 37 mutations distributed over the trimeric protein domains. Notably, fifteen of these mutations reside in the receptor-binding domain of the spike glycoprotein, which may alter transmissibility and infectivity. Additionally, the omicron spike evades neutralization more efficiently than the delta spike. Most of the therapeutic antibodies are ineffective against the omicron variant, and double immunization with BioNTech-Pfizer (BNT162b2) might not adequately protect against severe disease induced by omicron B.1.1.529. So far, no efficient antiviral drugs are available against omicron. The present study identified the promising inhibitors from seaweed's bioactive compounds to inhibit the omicron variant B.1.1.529. We have also compared the seaweed's compounds with the standard drugs ceftriaxone and cefuroxime, which were suggested as beneficial antiviral drugs in COVID-19 treatment. Our molecular docking analysis revealed that caffeic acid hexoside (-6.4 kcal/mol; RMSD = 2.382 Å) and phloretin (-6.3 kcal/mol; RMSD = 0.061 Å) from Sargassum wightii (S. wightii) showed the inhibitory effect against the crucial residues ASN417, SER496, TYR501, and HIS505, which are supported for the inviolable omicron and angiotensin-converting enzyme II (ACE2) receptor interaction. Cholestan-3-ol, 2-methylene-, (3beta, 5 alpha) (CMBA) (-6.0 kcal/mol; RMSD = 3.074 Å) from Corallina officinalis (C. officinalis) manifested the strong inhibitory effect against the omicron RBD mutated residues LEU452 and ALA484, was magnificently observed as the essential residues in Indian delta variant B.1.617.2 previously. The standard drugs (ceftriaxone and cefuroxime) showed no or less inhibitory effect against RBD of omicron B.1.1.529. The present study also emphasized the pharmacological properties of the considered chemical compounds. The results could be used to develop potent seaweed-based antiviral drugs and/or dietary supplements to treat omicron B.1.1529-infected patients.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Gene Expression Regulation, Viral/drug effects , Molecular Docking Simulation , SARS-CoV-2/metabolism , Seaweed/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Humans , Mutation , Protein Binding , Protein Conformation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
3.
Sci Rep ; 11(1): 24442, 2021 12 24.
Article in English | MEDLINE | ID: covidwho-1577650

ABSTRACT

Therapeutic interventions targeting viral infections remain a significant challenge for both the medical and scientific communities. While specific antiviral agents have shown success as therapeutics, viral resistance inevitably develops, making many of these approaches ineffective. This inescapable obstacle warrants alternative approaches, such as the targeting of host cellular factors. Respiratory syncytial virus (RSV), the major respiratory pathogen of infants and children worldwide, causes respiratory tract infection ranging from mild upper respiratory tract symptoms to severe life-threatening lower respiratory tract disease. Despite the fact that the molecular biology of the virus, which was originally discovered in 1956, is well described, there is no vaccine or effective antiviral treatment against RSV infection. Here, we demonstrate that targeting host factors, specifically, mTOR signaling, reduces RSV protein production and generation of infectious progeny virus. Further, we show that this approach can be generalizable as inhibition of mTOR kinases reduces coronavirus gene expression, mRNA transcription and protein production. Overall, defining virus replication-dependent host functions may be an effective means to combat viral infections, particularly in the absence of antiviral drugs.


Subject(s)
Coronavirus/metabolism , Respiratory Syncytial Virus, Human/metabolism , TOR Serine-Threonine Kinases/metabolism , Viral Proteins/metabolism , A549 Cells , Coronavirus/drug effects , Coronavirus/genetics , Gene Expression Regulation, Viral/drug effects , Humans , Protein Biosynthesis/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , RNA Interference , RNA, Small Interfering/metabolism , Rapamycin-Insensitive Companion of mTOR Protein/antagonists & inhibitors , Rapamycin-Insensitive Companion of mTOR Protein/genetics , Rapamycin-Insensitive Companion of mTOR Protein/metabolism , Regulatory-Associated Protein of mTOR/antagonists & inhibitors , Regulatory-Associated Protein of mTOR/genetics , Regulatory-Associated Protein of mTOR/metabolism , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/pathology , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Virus, Human/drug effects , Respiratory Syncytial Virus, Human/isolation & purification , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/genetics , Viral Proteins/genetics
4.
Front Immunol ; 12: 700184, 2021.
Article in English | MEDLINE | ID: covidwho-1365542

ABSTRACT

Coronavirus disease 2019 (COVID-19), which has high incidence rates with rapid rate of transmission, is a pandemic that spread across the world, resulting in more than 3,000,000 deaths globally. Currently, several drugs have been used for the clinical treatment of COVID-19, such as antivirals (radecivir, baritinib), monoclonal antibodies (tocilizumab), and glucocorticoids (dexamethasone). Accumulating evidence indicates that long noncoding RNAs (lncRNAs) are essential regulators of virus infections and antiviral immune responses including biological processes that are involved in the regulation of COVID-19 and subsequent disease states. Upon viral infections, cellular lncRNAs directly regulate viral genes and influence viral replication and pathology through virus-mediated changes in the host transcriptome. Additionally, several host lncRNAs could help the occurrence of viral immune escape by inhibiting type I interferons (IFN-1), while others could up-regulate IFN-1 production to play an antiviral role. Consequently, understanding the expression and function of lncRNAs during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection will provide insights into the development of lncRNA-based methods. In this review, we summarized the current findings of lncRNAs in the regulation of the strong inflammatory response, immune dysfunction and thrombosis induced by SARS-CoV-2 infection, discussed the underlying mechanisms, and highlighted the therapeutic challenges of COVID-19 treatment and its future research directions.


Subject(s)
COVID-19/immunology , Host Microbial Interactions/genetics , Immunity, Innate/genetics , RNA, Long Noncoding/metabolism , Thrombosis/immunology , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Biomarkers/analysis , COVID-19/complications , COVID-19/drug therapy , COVID-19/genetics , COVID-19 Testing/methods , Cytokines/genetics , Cytokines/metabolism , Gene Expression Regulation, Viral/drug effects , Gene Expression Regulation, Viral/immunology , Host Microbial Interactions/drug effects , Host Microbial Interactions/immunology , Humans , Immune Evasion/genetics , Pandemics/prevention & control , RNA, Long Noncoding/analysis , RNA, Long Noncoding/antagonists & inhibitors , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Signal Transduction/genetics , Signal Transduction/immunology , Thrombosis/genetics , Thrombosis/virology , Virus Replication/drug effects , Virus Replication/genetics , Virus Replication/immunology
5.
STAR Protoc ; 2(4): 100781, 2021 12 17.
Article in English | MEDLINE | ID: covidwho-1356489

ABSTRACT

We present a protocol for analyzing the impact of SARS-CoV-2 proteins in interferon signaling using luciferase reporter assays. Here, the induction of defined promoters can be quantitatively assessed with high sensitivity and broad linear range. The results are similar to those obtained using qPCR to measure endogenous mRNA induction. The assay requires stringent normalization and confirmation of the results in more physiological settings. The protocol is adaptable for other viruses and other innate immune stimuli. For complete details on the use and execution of this protocol, please refer to Hayn et al. (2021).


Subject(s)
COVID-19/pathology , Gene Expression Regulation, Viral/drug effects , Interferons/pharmacology , Luciferases/metabolism , RNA, Messenger/metabolism , SARS-CoV-2/metabolism , Viral Proteins/metabolism , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/virology , Humans , Luciferases/genetics , Promoter Regions, Genetic , RNA, Messenger/genetics , SARS-CoV-2/drug effects , Viral Proteins/genetics
6.
FASEB J ; 35(8): e21774, 2021 08.
Article in English | MEDLINE | ID: covidwho-1331587

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease 2019 (COVID-19), one of the most challenging global pandemics of the modern era. Potential treatment strategies against COVID-19 are yet to be devised. It is crucial that antivirals that interfere with the SARS-CoV-2 life cycle be identified and developed. 3-Chymotrypsin-like protease (3CLpro) is an attractive antiviral drug target against SARS-CoV-2, and coronaviruses in general, because of its role in the processing of viral polyproteins. Inhibitors of 3CLpro activity are screened in enzyme assays before further development of the most promising leads. Dimethyl sulfoxide (DMSO) is a common additive used in such assays and enhances the solubility of assay components. However, it may also potentially affect the stability and efficiency of 3CLpro but, to date, this effect had not been analyzed in detail. Here, we investigated the effect of DMSO on 3CLpro-catalyzed reaction. While DMSO (5%-20%) decreased the optimum temperature of catalysis and thermodynamic stability of 3CLpro, it only marginally affected the kinetic stability of the enzyme. Increasing the DMSO concentration up to 20% improved the catalytic efficiency and peptide-binding affinity of 3CLpro. At such high DMSO concentration, the solubility and stability of peptide substrate were improved because of reduced aggregation. In conclusion, we recommend 20% DMSO as the minimum concentration to be used in screens of 3CLpro inhibitors as lead compounds for the development of antiviral drugs against COVID-19.


Subject(s)
COVID-19/virology , Coronavirus 3C Proteases/metabolism , Dimethyl Sulfoxide/pharmacology , Gene Expression Regulation, Enzymologic/drug effects , Gene Expression Regulation, Viral/drug effects , SARS-CoV-2/enzymology , Computer Simulation , Coronavirus 3C Proteases/genetics , Humans , Microfluidic Analytical Techniques , Peptides/metabolism , Protein Stability
7.
Expert Rev Clin Pharmacol ; 14(10): 1305-1315, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1322577

ABSTRACT

BACKGROUND: The high transmission and pathogenicity of SARS-CoV-2 has led to a pandemic that has halted the world's economy and health. The newly evolved strains and scarcity of vaccines has worsened the situation. The main protease (Mpro) of SARS-CoV-2 can act as a potential target due to its role in viral replication and conservation level. METHODS: In this study, we have enlisted more than 1100 phytochemicals from Asian plants based on deep literature mining. The compounds library was screened against the Mpro of SARS-CoV-2. RESULTS: The selected three ligands, Flemichin, Delta-Oleanolic acid, and Emodin 1-O-beta-D-glucoside had a binding energy of -8.9, -8.9, -8.7 KJ/mol respectively. The compounds bind to the active groove of the main protease at; Cys145, Glu166, His41, Met49, Pro168, Met165, Gln189. The multiple descriptors from the simulation study; root mean square deviation, root mean square fluctuation, radius of gyration, hydrogen bond, solvent accessible surface area confirms the stable nature of the protein-ligand complexes. Furthermore, post-md analysis confirms the rigidness in the docked poses over the simulation trajectories. CONCLUSIONS: Our combinatorial drug design approaches may help researchers to identify suitable drug candidates against SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Drug Discovery , Phytochemicals/pharmacology , SARS-CoV-2/enzymology , Viral Proteases/metabolism , Antiviral Agents/chemistry , Databases, Chemical , Gene Expression Regulation, Viral/drug effects , Molecular Docking Simulation , Molecular Structure , Phytochemicals/chemistry , Viral Proteases/genetics
8.
Mar Drugs ; 19(5)2021 Apr 25.
Article in English | MEDLINE | ID: covidwho-1201406

ABSTRACT

The high risk of morbidity and mortality associated with SARS-CoV-2 has accelerated the development of many potential vaccines. However, these vaccines are designed against SARS-CoV-2 isolated in Wuhan, China, and thereby may not be effective against other SARS-CoV-2 variants such as the United Kingdom variant (VUI-202012/01). The UK SARS-CoV-2 variant possesses D614G mutation in the Spike protein, which impart it a high rate of infection. Therefore, newer strategies are warranted to design novel vaccines and drug candidates specifically designed against the mutated forms of SARS-CoV-2. One such strategy is to target ACE2 (angiotensin-converting enzyme2)-Spike protein RBD (receptor binding domain) interaction. Here, we generated a homology model of Spike protein RBD of SARS-CoV-2 UK strain and screened a marine seaweed database employing different computational approaches. On the basis of high-throughput virtual screening, standard precision, and extra precision molecular docking, we identified BE011 (Dieckol) as the most potent compounds against RBD. However, Dieckol did not display drug-like properties, and thus different derivatives of it were generated in silico and evaluated for binding potential and drug-like properties. One Dieckol derivative (DK07) displayed good binding affinity for RBD along with acceptable physicochemical, pharmacokinetic, drug-likeness, and ADMET properties. Analysis of the RBD-DK07 interaction suggested the formation of hydrogen bonds, electrostatic interactions, and hydrophobic interactions with key residues mediating the ACE2-RBD interaction. Molecular dynamics simulation confirmed the stability of the RBD-DK07 complex. Free energy calculations suggested the primary role of electrostatic and Van der Waals' interaction in stabilizing the RBD-DK07 complex. Thus, DK07 may be developed as a potential inhibitor of the RBD-ACE2 interaction. However, these results warrant further validation by in vitro and in vivo studies.


Subject(s)
Benzofurans/chemistry , Benzofurans/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Computer Simulation , Gene Expression Regulation, Viral/drug effects , Molecular Structure , Spike Glycoprotein, Coronavirus/metabolism
9.
Curr Med Sci ; 41(2): 297-305, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1193158

ABSTRACT

Since the outbreak of the novel corona virus disease 2019 (COVID-19) at the end of 2019, specific antiviral drugs have been lacking. A Chinese patent medicine Toujiequwen granules has been promoted in the treatment of COVID-19. The present study was designed to reveal the molecular mechanism of Toujiequwen granules against COVID-19. A network pharmacological method was applied to screen the main active ingredients of Toujiequwen granules. Network analysis of 149 active ingredients and 330 drug targets showed the most active ingredient interacting with many drug targets is quercetin. Drug targets most affected by the active ingredients were PTGS2, PTGS1, and DPP4. Drug target disease enrichment analysis showed drug targets were significantly enriched in cardiovascular diseases and digestive tract diseases. An "active ingredient-target-disease" network showed that 57 active ingredients from Toujiequwen granules interacted with 15 key targets of COVID-19. There were 53 ingredients that could act on DPP4, suggesting that DPP4 may become a potential new key target for the treatment of COVID-19. GO analysis results showed that key targets were mainly enriched in the cellular response to lipopolysaccharide, cytokine activity and other functions. KEGG analysis showed they were mainly concentrated in viral protein interaction with cytokine and cytokine receptors and endocrine resistance pathway. The evidence suggests that Toujiequwen granules might play an effective role by improving the symptoms of underlying diseases in patients with COVID-19 and multi-target interventions against multiple signaling pathways related to the pathogenesis of COVID-19.


Subject(s)
COVID-19/drug therapy , Drugs, Chinese Herbal/pharmacology , Medicine, Chinese Traditional , SARS-CoV-2/genetics , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/genetics , COVID-19/virology , Cyclooxygenase 1/genetics , Cyclooxygenase 2/genetics , Dipeptidyl Peptidase 4/genetics , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/classification , Gene Expression Regulation, Viral/drug effects , Humans , Quercetin/genetics , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Signal Transduction/drug effects
10.
PLoS Biol ; 19(3): e3001158, 2021 03.
Article in English | MEDLINE | ID: covidwho-1156073

ABSTRACT

Since its emergence in December 2019, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread globally and become a major public health burden. Despite its close phylogenetic relationship to SARS-CoV, SARS-CoV-2 exhibits increased human-to-human transmission dynamics, likely due to efficient early replication in the upper respiratory epithelium of infected individuals. Since different temperatures encountered in the human upper and lower respiratory tract (33°C and 37°C, respectively) have been shown to affect the replication kinetics of several respiratory viruses, as well as host innate immune response dynamics, we investigated the impact of temperature on SARS-CoV-2 and SARS-CoV infection using the primary human airway epithelial cell culture model. SARS-CoV-2, in contrast to SARS-CoV, replicated to higher titers when infections were performed at 33°C rather than 37°C. Although both viruses were highly sensitive to type I and type III interferon pretreatment, a detailed time-resolved transcriptome analysis revealed temperature-dependent interferon and pro-inflammatory responses induced by SARS-CoV-2 that were inversely proportional to its replication efficiency at 33°C or 37°C. These data provide crucial insight on pivotal virus-host interaction dynamics and are in line with characteristic clinical features of SARS-CoV-2 and SARS-CoV, as well as their respective transmission efficiencies.


Subject(s)
Gene Expression Profiling/methods , Gene Expression Regulation, Viral/genetics , SARS Virus/genetics , SARS-CoV-2/genetics , Animals , Antiviral Agents/pharmacology , Cells, Cultured , Chlorocebus aethiops , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Epithelial Cells/virology , Gene Expression Regulation, Viral/drug effects , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Interferons/pharmacology , SARS Virus/drug effects , SARS Virus/physiology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Species Specificity , Temperature , Vero Cells , Virus Replication/drug effects , Virus Replication/genetics
11.
Gene ; 771: 145368, 2021 Mar 01.
Article in English | MEDLINE | ID: covidwho-1077902

ABSTRACT

Coronavirus disease-2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has become an immense threat to global public health. In this study, we performed complete genome sequencing of a SARS-CoV-2 isolate. More than 67,000 genome sequences were further inspected from Global Initiative on Sharing All Influenza Data (GISAID). Using several in silico techniques, we proposed prospective therapeutics against this virus. Through meticulous analysis, several conserved and therapeutically suitable regions of SARS-CoV-2 such as RNA-dependent RNA polymerase (RdRp), Spike (S) and Membrane glycoprotein (M) coding genes were selected. Both S and M were chosen for the development of a chimeric vaccine that can generate memory B and T cells. siRNAs were also designed for S and M gene silencing. Moreover, six new drug candidates were suggested that might inhibit the activity of RdRp. Since SARS-CoV-2 and SARS-CoV-1 have 82.30% sequence identity, a Gene Expression Omnibus (GEO) dataset of Severe Acute Respiratory Syndrome (SARS) patients were analyzed. In this analysis, 13 immunoregulatory genes were found that can be used to develop type 1 interferon (IFN) based therapy. The proposed vaccine, siRNAs, drugs and IFN based analysis of this study will accelerate the development of new treatments.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Computational Biology/methods , Gene Expression Profiling/methods , SARS-CoV-2/genetics , Whole Genome Sequencing/methods , Antiviral Agents/therapeutic use , COVID-19/virology , Computer Simulation , Conserved Sequence , Coronavirus M Proteins/genetics , Drug Design , Female , Gene Expression Regulation, Viral/drug effects , Humans , Interferons/pharmacology , Middle Aged , Prospective Studies , RNA-Dependent RNA Polymerase/genetics , SARS-CoV-2/classification , Sequence Analysis, RNA , Spike Glycoprotein, Coronavirus/genetics
12.
Genomics ; 113(1 Pt 1): 331-343, 2021 01.
Article in English | MEDLINE | ID: covidwho-972544

ABSTRACT

An outbreak, caused by an RNA virus, SARS-CoV-2 named COVID-19 has become pandemic with a magnitude which is daunting to all public health institutions in the absence of specific antiviral treatment. Surface glycoprotein and nucleocapsid phosphoprotein are two important proteins of this virus facilitating its entry into host cell and genome replication. Small interfering RNA (siRNA) is a prospective tool of the RNA interference (RNAi) pathway for the control of human viral infections by suppressing viral gene expression through hybridization and neutralization of target complementary mRNA. So, in this study, the power of RNA interference technology was harnessed to develop siRNA molecules against specific target genes namely, nucleocapsid phosphoprotein gene and surface glycoprotein gene. Conserved sequence from 139 SARS-CoV-2 strains from around the globe was collected to construct 78 siRNA that can inactivate nucleocapsid phosphoprotein and surface glycoprotein genes. Finally, based on GC content, free energy of folding, free energy of binding, melting temperature, efficacy prediction and molecular docking analysis, 8 siRNA molecules were selected which are proposed to exert the best action. These predicted siRNAs should effectively silence the genes of SARS-CoV-2 during siRNA mediated treatment assisting in the response against SARS-CoV-2.


Subject(s)
COVID-19/therapy , Computational Chemistry , Coronavirus Nucleocapsid Proteins/genetics , Drug Design , Genetic Therapy/methods , Molecular Docking Simulation , RNA Interference , RNA, Messenger/antagonists & inhibitors , RNA, Small Interfering/chemistry , RNA, Viral/antagonists & inhibitors , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Argonaute Proteins/chemistry , Argonaute Proteins/genetics , Base Composition , COVID-19/drug therapy , COVID-19/virology , Evolution, Molecular , Gene Expression Regulation, Viral/drug effects , Humans , Pandemics , Phosphoproteins/genetics , Phylogeny , RNA Folding , RNA, Guide/chemistry , RNA, Guide/genetics , RNA, Messenger/genetics , RNA, Small Interfering/pharmacology , RNA, Small Interfering/therapeutic use , RNA, Viral/genetics , SARS-CoV-2/drug effects , Sequence Alignment , Thermodynamics
13.
Clin Epigenetics ; 12(1): 156, 2020 10 21.
Article in English | MEDLINE | ID: covidwho-883596

ABSTRACT

Epigenetics is a relatively new field of science that studies the genetic and non-genetic aspects related to heritable phenotypic changes, frequently caused by environmental and metabolic factors. In the host, the epigenetic machinery can regulate gene expression through a series of reversible epigenetic modifications, such as histone methylation and acetylation, DNA/RNA methylation, chromatin remodeling, and non-coding RNAs. The coronavirus disease 19 (COVID-19) is a highly transmittable and pathogenic viral infection. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which emerged in Wuhan, China, and spread worldwide, causes it. COVID-19 severity and consequences largely depend on patient age and health status. In this review, we will summarize and comparatively analyze how viruses regulate the host epigenome. Mainly, we will be focusing on highly pathogenic respiratory RNA virus infections such as coronaviruses. In this context, epigenetic alterations might play an essential role in the onset of coronavirus disease complications. Although many therapeutic approaches are under study, more research is urgently needed to identify effective vaccine or safer chemotherapeutic drugs, including epigenetic drugs, to cope with this viral outbreak and to develop pre- and post-exposure prophylaxis against COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/physiology , Coronavirus Infections/drug therapy , Coronavirus Infections/genetics , Epigenesis, Genetic , Gene Expression Regulation, Viral , Pneumonia, Viral/drug therapy , Pneumonia, Viral/genetics , COVID-19 , Coronavirus Infections/immunology , Cytokines/genetics , Cytokines/immunology , Gene Expression Regulation, Viral/drug effects , Host-Pathogen Interactions , Humans , Inflammation/immunology , Pandemics , Pneumonia, Viral/immunology , RNA Processing, Post-Transcriptional , SARS-CoV-2
14.
Br J Nutr ; 125(3): 275-293, 2021 02 14.
Article in English | MEDLINE | ID: covidwho-843886

ABSTRACT

In December 2019, a novel human-infecting coronavirus, named Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), was recognised to cause a pneumonia epidemic outbreak with different degrees of severity in Wuhan, Hubei Province in China. Since then, this epidemic has spread worldwide; in Europe, Italy has been involved. Effective preventive and therapeutic strategies are absolutely required to block this serious public health concern. Unfortunately, few studies about SARS-CoV-2 concerning its immunopathogenesis and treatment are available. On the basis of the assumption that the SARS-CoV-2 is genetically related to SARS-CoV (about 82 % of genome homology) and that its characteristics, like the modality of transmission or the type of the immune response it may stimulate, are still poorly known, a literature search was performed to identify the reports assessing these elements in patients with SARS-CoV-induced infection. Therefore, we have analysed: (1) the structure of SARS-CoV-2 and SARS-CoV; (2) the clinical signs and symptoms and pathogenic mechanisms observed during the development of acute respiratory syndrome and the cytokine release syndrome; (3) the modification of the cell microRNome and of the immune response in patients with SARS infection; and (4) the possible role of some fat-soluble compounds (such as vitamins A, D and E) in modulating directly or indirectly the replication ability of SARS-CoV-2 and host immune response.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/therapy , COVID-19/virology , Immunologic Factors/therapeutic use , SARS-CoV-2 , Gene Expression Regulation, Viral/drug effects , Gene Expression Regulation, Viral/physiology , Genome, Viral , Humans , Severe Acute Malnutrition/drug therapy , Severe Acute Malnutrition/etiology , Severity of Illness Index , Viral Proteins , Vitamins/administration & dosage , Vitamins/therapeutic use
15.
Angew Chem Int Ed Engl ; 60(1): 432-438, 2021 01 04.
Article in English | MEDLINE | ID: covidwho-774564

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 has become a global threat. Understanding the underlying mechanisms and developing innovative treatments are extremely urgent. G-quadruplexes (G4s) are important noncanonical nucleic acid structures with distinct biofunctions. Four putative G4-forming sequences (PQSs) in the SARS-CoV-2 genome were studied. One of them (RG-1), which locates in the coding sequence region of SARS-CoV-2 nucleocapsid phosphoprotein (N), has been verified to form a stable RNA G4 structure in live cells. G4-specific compounds, such as PDP (pyridostatin derivative), can stabilize RG-1 G4 and significantly reduce the protein levels of SARS-CoV-2 N by inhibiting its translation both in vitro and in vivo. This result is the first evidence that PQSs in SARS-CoV-2 can form G4 structures in live cells, and that their biofunctions can be regulated by a G4-specific stabilizer. This finding will provide new insights into developing novel antiviral drugs against COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , G-Quadruplexes/drug effects , RNA, Viral/drug effects , SARS-CoV-2/drug effects , Drug Evaluation, Preclinical , Gene Expression Regulation, Viral/drug effects , Genome, Viral , Humans , Nucleocapsid Proteins/chemistry , Nucleocapsid Proteins/drug effects , Protein Folding , SARS-CoV-2/genetics , Small Molecule Libraries , Temperature
16.
J Mol Biol ; 432(21): 5843-5847, 2020 10 02.
Article in English | MEDLINE | ID: covidwho-753245

ABSTRACT

SARS-CoV-2 uses -1 programmed ribosomal frameshifting (-1 PRF) to control expression of key viral proteins. Because modulating -1 PRF can attenuate the virus, ligands binding to the RNA pseudoknot that stimulates -1 PRF may have therapeutic potential. Mutations in the pseudoknot have occurred during the pandemic, but how they affect -1 PRF efficiency and ligand activity is unknown. Studying a panel of six mutations in key regions of the pseudoknot, we found that most did not change -1 PRF levels, even when base-pairing was disrupted, but one led to a striking 3-fold decrease, suggesting SARS-CoV-2 may be less sensitive to -1 PRF modulation than expected. Examining the effects of a small-molecule -1 PRF inhibitor active against SARS-CoV-2, it had a similar effect on all mutants tested, regardless of basal -1 PRF efficiency, indicating that anti-frameshifting activity can be resistant to natural pseudoknot mutations. These results have important implications for therapeutic strategies targeting SARS-CoV-2 through modulation of -1 PRF.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Frameshifting, Ribosomal/drug effects , Gene Expression Regulation, Viral/drug effects , Pneumonia, Viral/drug therapy , Small Molecule Libraries/pharmacology , Antiviral Agents/chemistry , Betacoronavirus/genetics , COVID-19 , Coronavirus Infections/virology , Humans , Ligands , Mutation/drug effects , Pandemics , Pneumonia, Viral/virology , RNA, Messenger/genetics , RNA, Viral/genetics , SARS-CoV-2 , Small Molecule Libraries/chemistry , Viral Proteins/genetics
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