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1.
Signal Transduct Target Ther ; 7(1): 26, 2022 01 27.
Article in English | MEDLINE | ID: covidwho-1655545

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the causative agent of the pandemic disease COVID-19, which is so far without efficacious treatment. The discovery of therapy reagents for treating COVID-19 are urgently needed, and the structures of the potential drug-target proteins in the viral life cycle are particularly important. SARS-CoV-2, a member of the Orthocoronavirinae subfamily containing the largest RNA genome, encodes 29 proteins including nonstructural, structural and accessory proteins which are involved in viral adsorption, entry and uncoating, nucleic acid replication and transcription, assembly and release, etc. These proteins individually act as a partner of the replication machinery or involved in forming the complexes with host cellular factors to participate in the essential physiological activities. This review summarizes the representative structures and typically potential therapy agents that target SARS-CoV-2 or some critical proteins for viral pathogenesis, providing insights into the mechanisms underlying viral infection, prevention of infection, and treatment. Indeed, these studies open the door for COVID therapies, leading to ways to prevent and treat COVID-19, especially, treatment of the disease caused by the viral variants are imperative.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Design/trends , Drug Repositioning , SARS-CoV-2/drug effects , Adrenal Cortex Hormones/chemistry , Adrenal Cortex Hormones/therapeutic use , Antibodies, Viral/chemistry , Antibodies, Viral/therapeutic use , Antiviral Agents/chemistry , Aptamers, Nucleotide/chemistry , Aptamers, Nucleotide/therapeutic use , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/therapeutic use , Humans , Models, Molecular , Nucleosides/chemistry , Nucleosides/therapeutic use , Protein Conformation , SARS-CoV-2/genetics , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , Virus Internalization/drug effects , Virus Release/drug effects , Virus Replication/drug effects
2.
Int J Mol Sci ; 23(1)2022 Jan 04.
Article in English | MEDLINE | ID: covidwho-1613825

ABSTRACT

(1R,5S)-1-Hydroxy-3,6-dioxa-bicyclo[3.2.1]octan-2-one, available by an efficient catalytic pyrolysis of cellulose, has been applied as a chiral building block in the synthesis of seven new nucleoside analogues, with structural modifications on the nucleobase moiety and on the carboxyl- derived unit. The inverted configuration by Mitsunobu reaction used in their synthesis was verified by 2D-NOESY correlations, supported by the optimized structure employing the DFT methods. An in silico screening of these compounds as inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase has been carried out in comparison with both remdesivir, a mono-phosphoramidate prodrug recently approved for COVID-19 treatment, and its ribonucleoside metabolite GS-441524. Drug-likeness prediction and data by docking calculation indicated compound 6 [=(3S,5S)-methyl 5-(hydroxymethyl)-3-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)tetrahydrofuran-3-carboxylate] as the best candidate. Furthermore, molecular dynamics simulation showed a stable interaction of structure 6 in RNA-dependent RNA polymerase (RdRp) complex and a lower average atomic fluctuation than GS-441524, suggesting a well accommodation in the RdRp binding pocket.


Subject(s)
Antiviral Agents/chemical synthesis , Cellulose/chemistry , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Nucleosides/chemical synthesis , SARS-CoV-2/enzymology , Adenosine/analogs & derivatives , Adenosine/chemistry , Adenosine/pharmacokinetics , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/pharmacokinetics , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/pharmacokinetics , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Computational Biology , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , Nucleosides/chemistry , Nucleosides/pharmacokinetics , Pyrolysis , SARS-CoV-2/drug effects
3.
Angew Chem Int Ed Engl ; 61(11): e202114619, 2022 03 07.
Article in English | MEDLINE | ID: covidwho-1544209

ABSTRACT

Since early 2020, scientists have strived to find an effective solution to fight SARS-CoV-2, in particular by developing reliable vaccines that inhibit the spread of the disease and repurposing drugs for combatting its effects on the human body. The antiviral prodrug Remdesivir is still the most widely used therapeutic during the early stages of the infection. However, the current synthetic routes rely on the use of protecting groups, air-sensitive reagents, and cryogenic conditions, thus impeding a cost-efficient supply to patients. We have, therefore, focused on the development of a straightforward, direct addition of (hetero)arenes to unprotected sugars. Here we report a silylium-catalyzed and completely stereoselective C-glycosylation that initially yields the open-chain polyols, which can be selectively cyclized to provide either the kinetic α-furanose or the thermodynamically favored ß-anomer. The method significantly expedites the synthesis of Remdesivir precursor GS-441524 after a subsequent Mn-catalyzed C-H oxidation and deoxycyanation.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Adenosine/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/chemical synthesis , Nucleosides/chemical synthesis , Adenosine/chemical synthesis , Adenosine/chemistry , Adenosine Monophosphate/chemical synthesis , Adenosine Monophosphate/chemistry , Alanine/chemical synthesis , Alanine/chemistry , Antiviral Agents/chemistry , COVID-19/drug therapy , Catalysis , Chemistry Techniques, Synthetic/economics , Chemistry Techniques, Synthetic/methods , Cyclization , Glycosylation , Humans , Models, Molecular , Nucleosides/chemistry , Stereoisomerism , Time Factors
4.
Nat Commun ; 12(1): 6777, 2021 11 22.
Article in English | MEDLINE | ID: covidwho-1528015

ABSTRACT

Lipid nanoparticle (LNP)-formulated mRNA vaccines were rapidly developed and deployed in response to the SARS-CoV-2 pandemic. Due to the labile nature of mRNA, identifying impurities that could affect product stability and efficacy is crucial to the long-term use of nucleic-acid based medicines. Herein, reversed-phase ion pair high performance liquid chromatography (RP-IP HPLC) was used to identify a class of impurity formed through lipid:mRNA reactions; such reactions are typically undetectable by traditional mRNA purity analytical techniques. The identified modifications render the mRNA untranslatable, leading to loss of protein expression. Specifically, electrophilic impurities derived from the ionizable cationic lipid component are shown to be responsible. Mechanisms implicated in the formation of reactive species include oxidation and subsequent hydrolysis of the tertiary amine. It thus remains critical to ensure robust analytical methods and stringent manufacturing control to ensure mRNA stability and high activity in LNP delivery systems.


Subject(s)
Drug Delivery Systems , Liposomes/chemistry , Nanoparticles/chemistry , RNA, Messenger/chemistry , Vaccine Potency , Aldehydes/chemistry , Chromatography, Liquid , Humans , Ions/chemistry , Lipids/chemistry , Nucleosides/chemistry , Oxidation-Reduction , Protein Biosynthesis , RNA Stability , /chemistry
5.
Nature ; 601(7893): 410-414, 2022 01.
Article in English | MEDLINE | ID: covidwho-1521758

ABSTRACT

The CVnCoV (CureVac) mRNA vaccine for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was recently evaluated in a phase 2b/3 efficacy trial in humans1. CV2CoV is a second-generation mRNA vaccine containing non-modified nucleosides but with optimized non-coding regions and enhanced antigen expression. Here we report the results of a head-to-head comparison of the immunogenicity and protective efficacy of CVnCoV and CV2CoV in non-human primates. We immunized 18 cynomolgus macaques with two doses of 12 µg lipid nanoparticle-formulated CVnCoV or CV2CoV or with sham (n = 6 per group). Compared with CVnCoV, CV2CoV induced substantially higher titres of binding and neutralizing antibodies, memory B cell responses and T cell responses as well as more potent neutralizing antibody responses against SARS-CoV-2 variants, including the Delta variant. Moreover, CV2CoV was found to be comparably immunogenic to the BNT162b2 (Pfizer) vaccine in macaques. Although CVnCoV provided partial protection against SARS-CoV-2 challenge, CV2CoV afforded more robust protection with markedly lower viral loads in the upper and lower respiratory tracts. Binding and neutralizing antibody titres were correlated with protective efficacy. These data demonstrate that optimization of non-coding regions can greatly improve the immunogenicity and protective efficacy of a non-modified mRNA SARS-CoV-2 vaccine in non-human primates.


Subject(s)
COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunogenicity, Vaccine , Nucleosides/chemistry , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology , /immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/standards , Female , Macaca fascicularis/immunology , Male , Nucleosides/genetics , Respiratory System/immunology , Respiratory System/virology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Vaccines, Synthetic/standards , Viral Load , /standards
6.
Molecules ; 26(5)2021 Mar 09.
Article in English | MEDLINE | ID: covidwho-1143539

ABSTRACT

A series of hitherto unknown (1,4-disubstituted-1,2,3-triazol)-(E)-2-methyl-but-2-enyl nucleosides phosphonate prodrugs bearing 4-substituted-1,2,3-triazoles were prepared in a straight approach through an olefin acyclic cross metathesis as the key synthetic step. All novel compounds were evaluated for their antiviral activities against HBV, HIV and SARS-CoV-2. Among these molecules, only compound 15j, a hexadecyloxypropyl (HDP)/(isopropyloxycarbonyl-oxymethyl)-ester (POC) prodrug, showed activity against HBV in Huh7 cell cultures with 62% inhibition at 10 µM, without significant cytotoxicity (IC50 = 66.4 µM in HepG2 cells, IC50 = 43.1 µM in HepG2 cells) at 10 µM.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Azo Compounds/chemistry , Nucleosides/chemistry , Organophosphonates/chemistry , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Alkenes/chemistry , Animals , Cell Line, Tumor , Chlorocebus aethiops , HIV-1/drug effects , Hepatitis B virus/drug effects , Humans , Magnetic Resonance Spectroscopy , Methylation , SARS-CoV-2/drug effects , Structure-Activity Relationship , Triazoles/chemistry , Vero Cells
7.
Molecules ; 26(4)2021 Feb 13.
Article in English | MEDLINE | ID: covidwho-1085052

ABSTRACT

Coronaviruses (CoVs) are positive-sense RNA enveloped viruses, members of the family Coronaviridae, that cause infections in a broad range of mammals including humans. Several CoV species lead to mild upper respiratory infections typically associated with common colds. However, three human CoV (HCoV) species: Severe Acute Respiratory Syndrome (SARS)-CoV-1, Middle East Respiratory Syndrome (MERS)-CoV, and SARS-CoV-2, are responsible for severe respiratory diseases at the origin of two recent epidemics (SARS and MERS), and of the current COronaVIrus Disease 19 (COVID-19), respectively. The easily transmissible SARS-CoV-2, emerging at the end of 2019 in China, spread rapidly worldwide, leading the World Health Organization (WHO) to declare COVID-19 a pandemic. While the world waits for mass vaccination, there is an urgent need for effective drugs as short-term weapons to combat the SARS-CoV-2 infection. In this context, the drug repurposing approach is a strategy able to guarantee positive results rapidly. In this regard, it is well known that several nucleoside-mimicking analogs and nucleoside precursors may inhibit the growth of viruses providing effective therapies for several viral diseases, including HCoV infections. Therefore, this review will focus on synthetic nucleosides and nucleoside precursors active against different HCoV species, paying great attention to SARS-CoV-2. This work covers progress made in anti-CoV therapy with nucleoside derivatives and provides insight into their main mechanisms of action.


Subject(s)
Antiviral Agents , COVID-19/drug therapy , Drug Repositioning , Nucleosides , SARS Virus/metabolism , SARS-CoV-2/metabolism , Severe Acute Respiratory Syndrome/drug therapy , Animals , Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , COVID-19/epidemiology , COVID-19/metabolism , Humans , Nucleosides/chemistry , Nucleosides/therapeutic use , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/metabolism
8.
Eur J Med Chem ; 214: 113233, 2021 Mar 15.
Article in English | MEDLINE | ID: covidwho-1056562

ABSTRACT

With Remdesivir being approved by FDA as a drug for the treatment of Corona Virus Disease 2019 (COVID-19), nucleoside drugs have once again received widespread attention in the medical community. Herein, we summarized modification of traditional nucleoside framework (sugar + base), traizole nucleosides, nucleoside analogues assembled by other drugs, macromolecule-modified nucleosides, and their bioactivity rules. 2'-"Ara"-substituted by -F or -CN group, and 3'-"ara" substituted by acetylenyl group can greatly influence their anti-tumor activities. Dideoxy dehydrogenation of 2',3'-sites can enhance antiviral efficiencies. Acyclic nucleosides and L-type nucleosides mainly represented antiviral capabilities. 5-F Substituted uracil analogues exihibit anti-tumor effects, and the substrates substituted by -I, -CF3, bromovinyl group usually show antiviral activities. The sugar coupled with 1-N of triazolid usually displays anti-tumor efficiencies, while the sugar coupled with 2-N of triazolid mainly represents antiviral activities. The nucleoside analogues assembled by cholesterol, polyethylene glycol, fatty acid and phospholipid would improve their bioavailabilities and bioactivities, or reduce their toxicities.


Subject(s)
Antineoplastic Agents/chemistry , Antiviral Agents/chemistry , Nucleosides/chemistry
9.
Eur J Med Chem ; 213: 113201, 2021 Mar 05.
Article in English | MEDLINE | ID: covidwho-1039337

ABSTRACT

The widespread nature of several viruses is greatly credited to their rapidly altering RNA genomes that enable the infection to persist despite challenges presented by host cells. Within the RNA genome of infections is RNA-dependent RNA polymerase (RdRp), which is an essential enzyme that helps in RNA synthesis by catalysing the RNA template-dependent development of phosphodiester bonds. Therefore, RdRp is an important therapeutic target in RNA virus-caused diseases, including SARS-CoV-2. In this review, we describe the promising RdRp inhibitors that have been launched or are currently in clinical studies for the treatment of RNA virus infections. Structurally, nucleoside inhibitors (NIs) bind to the RdRp protein at the enzyme active site, and nonnucleoside inhibitors (NNIs) bind to the RdRp protein at allosteric sites. By reviewing these inhibitors, more precise guidelines for the development of more promising anti-RNA virus drugs should be set, and due to the current health emergency, they will eventually be used for COVID-19 treatment.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Drug Repositioning , Enzyme Inhibitors/therapeutic use , Animals , Antiviral Agents/chemistry , COVID-19/epidemiology , Enzyme Inhibitors/chemistry , Humans , Nucleosides/chemistry , Nucleosides/therapeutic use , Pandemics , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology
10.
Antimicrob Agents Chemother ; 65(1)2020 12 16.
Article in English | MEDLINE | ID: covidwho-1015593

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a serious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or CoV-2). Some reports claimed certain nucleoside analogs to be active against CoV-2 and thus needed confirmation. Here, we evaluated a panel of compounds and identified novel nucleoside analogs with antiviral activity against CoV-2 and HCoV-OC43 while ruling out others. Of significance, sofosbuvir demonstrated no antiviral effect against CoV-2, and its triphosphate did not inhibit CoV-2 RNA polymerase.


Subject(s)
Antiviral Agents/pharmacology , Drug Repositioning/methods , Nucleosides/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/toxicity , Cell Line , Chlorocebus aethiops , Coronavirus OC43, Human/drug effects , Drug Evaluation, Preclinical , Humans , Nucleosides/chemistry , Nucleosides/toxicity , Propanolamines/pharmacology , Sofosbuvir/pharmacology , Vero Cells
11.
Comput Biol Med ; 130: 104185, 2021 03.
Article in English | MEDLINE | ID: covidwho-987393

ABSTRACT

Coronaviruses are known to infect respiratory tract and intestine. These viruses possess highly conserved viral macro domain A1pp having adenosine diphosphate (ADP)-ribose binding and phosphatase activity sites. A1pp inhibits adenosine diphosphate (ADP)-ribosylation in the host and promotes viral infection and pathogenesis. We performed in silico screening of FDA approved drugs and nucleoside analogue library against the recently reported crystal structure of SARS-CoV-2 A1pp domain. Docking scores and interaction profile analyses exhibited strong binding affinity of eleven FDA approved drugs and five nucleoside analogues NA1 (-13.84), nadide (-13.65), citicholine (-13.54), NA2 (-12.42), and NA3 (-12.27). The lead compound NA1 exhibited significant hydrogen bonding and hydrophobic interaction at the natural substrate binding site. The root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent accessible surface (SASA), hydrogen bond formation, principle component analysis, and free energy landscape calculations for NA1 bound protein displayed stable complex formation in 100 ns molecular dynamics simulation, compared to unbound macro domain and natural substrate adenosine-5-diphosphoribose bound macro domain that served as a positive control. The molecular mechanics Poisson-Boltzmann surface area analysis of NA1 demonstrated binding free energy of -175.978 ± 0.401 kJ/mol in comparison to natural substrate which had binding free energy of -133.403 ± 14.103 kJ/mol. In silico analysis by modelling tool ADMET and prediction of biological activity of these compounds further validated them as putative therapeutic molecules against SARS-CoV-2. Taken together, this study offers NA1 as a lead SARS-CoV-2 A1pp domain inhibitor for future testing and development as therapeutics against human coronavirus.


Subject(s)
Antiviral Agents/chemistry , COVID-19/drug therapy , Coronavirus Papain-Like Proteases , Molecular Docking Simulation , Nucleosides/chemistry , SARS-CoV-2/chemistry , Antiviral Agents/therapeutic use , Binding Sites , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Coronavirus Papain-Like Proteases/chemistry , Drug Approval , Humans , Nucleosides/therapeutic use , Protein Binding , United States , United States Food and Drug Administration
12.
Phys Chem Chem Phys ; 22(48): 28115-28122, 2020 Dec 23.
Article in English | MEDLINE | ID: covidwho-963795

ABSTRACT

Repurposed drugs are now considered as attractive therapeutics against COVID-19. It is shown that Remdesivir, a nucleoside drug that was originally invented for the Ebola virus, is effective in suppressing the replication of SARS-CoV-2 that causes COVID-19. Similarly, Galidesivir, Favipiravir, Ribavirin, N4-hydroxycytidine (EIDD-1931), and EIDD-2801 (a prodrug of EIDD-1931) were also found to be effective against COVID-19. However, the mechanisms of action of these drugs are not yet fully understood. For example, in some experimental studies, these drugs were proposed to act as a RNA-chain terminator, while in other studies, these were proposed to induce base-pair mutations above the error catastrophe limit to stall the replication of the viral RNA. To understand the mutagenic effects of these drugs, the role of different tautomers in their base-pairing abilities is studied here in detail by employing a reliable dispersion-corrected density functional theoretic method. It is found that Remdesivir and Galidesivir can adopt both amino and imino tautomeric conformations to base-pair with RNA bases. While the insertions of G and U are preferred against the amino tautomers of these drugs, the insertion of C is mainly possible against the imino tautomers. However, although Favipiravir and Ribavirin can make stable base pair interactions by using their keto and enol tautomers, the formation of the latter pairs would be less probable due to the endothermic nature of the products. Interestingly, the insertions of all of the RNA bases are found to be possible against the keto tautomer of Favipiravir, while the keto tautomer of Ribavirin has a clear preference for G. Remarkably, due to the negligible difference in the stability of EIDD-2801 and EIDD-1931, these tautomers would coexist in the biological environment. The insertion of G is found to be preferred against EIDD-1931 and the incorporations of U, A, and G are preferred opposite EIDD-2801. These findings suggest that base-pair mutations are the main causes of the antiviral properties of these drugs.


Subject(s)
Antiviral Agents/chemistry , Base Pairing , Mutagens/chemistry , Nucleosides/chemistry , RNA/chemistry , COVID-19/drug therapy , Density Functional Theory , Isomerism , Models, Chemical , SARS-CoV-2/drug effects , Thermodynamics
13.
Molecules ; 25(7)2020 Mar 27.
Article in English | MEDLINE | ID: covidwho-831217

ABSTRACT

For decades, nucleosides and nucleotides have formed the cornerstone of antiviral, antiparasitic and anticancer therapeutics and have been used as tools in exploring nucleic acid structure and function [...].


Subject(s)
Nucleic Acids/chemistry , Nucleosides/chemistry , Nucleotides/chemistry , Anti-Bacterial Agents/pharmacology , Antiprotozoal Agents/pharmacology , Antiviral Agents/pharmacology , Computational Biology , Humans , Nucleosides/analogs & derivatives , Nucleosides/metabolism , Nucleosides/pharmacology , Nucleotides/metabolism
14.
Eur J Med Chem ; 201: 112557, 2020 Sep 01.
Article in English | MEDLINE | ID: covidwho-597389

ABSTRACT

The spreading of new viruses is known to provoke global human health threat. The current COVID-19 pandemic caused by the recently emerged coronavirus SARS-CoV-2 is one significant and unfortunate example of what the world will have to face in the future with emerging viruses in absence of appropriate treatment. The discovery of potent and specific antiviral inhibitors and/or vaccines to fight these massive outbreaks is an urgent research priority. Enzymes involved in the capping pathway of viruses and more specifically RNA N7- or 2'O-methyltransferases (MTases) are now admitted as potential targets for antiviral chemotherapy. We designed bisubstrate inhibitors by mimicking the transition state of the 2'-O-methylation of the cap RNA in order to block viral 2'-O MTases. This work resulted in the synthesis of 16 adenine dinucleosides with both adenosines connected by various nitrogen-containing linkers. Unexpectedly, all the bisubstrate compounds were barely active against 2'-O MTases of several flaviviruses or SARS-CoV but surprisingly, seven of them showed efficient and specific inhibition against SARS-CoV N7-MTase (nsp14) in the micromolar to submicromolar range. The most active nsp14 inhibitor identified is as potent as but particularly more specific than the broad-spectrum MTase inhibitor, sinefungin. Molecular docking suggests that the inhibitor binds to a pocket formed by the S-adenosyl methionine (SAM) and cap RNA binding sites, conserved among SARS-CoV nsp14. These dinucleoside SAM analogs will serve as starting points for the development of next inhibitors for SARS-CoV-2 nsp14 N7-MTase.


Subject(s)
Coronavirus Infections/drug therapy , Exoribonucleases/antagonists & inhibitors , Methyltransferases/antagonists & inhibitors , Nucleosides/chemistry , Pneumonia, Viral/drug therapy , RNA Caps/metabolism , S-Adenosylmethionine/analogs & derivatives , S-Adenosylmethionine/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Adenine/chemistry , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Exoribonucleases/metabolism , Humans , Methylation , Methyltransferases/metabolism , Molecular Docking Simulation , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , RNA Caps/chemistry , RNA Caps/genetics , RNA, Viral/genetics , RNA, Viral/metabolism , SARS-CoV-2 , Viral Nonstructural Proteins/metabolism
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