Antivirals Against Coronaviruses: Candidate Drugs for SARS-CoV-2 Treatment?

Santos, Igor Andrade; Grosche, Victória Riquena; Bergamini, Fernando R.G.; Sabino-Silva, Robinson; Jardim, Ana Carolina Gomes

doi:10.3389/fmicb.2020.01818

Cited by 91 publications

(59 citation statements)

References 246 publications

(324 reference statements)

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“…It was effective against HCoV-NL63 at the early stages of HCoV replication [ 128 ] and inhibited replication of SARS-CoV-1 at non-toxic doses [ 127 ]. Although no experimental data on its effect on SARS-CoV-2 are currently available, this nucleoside analog is among the drugs to be considered for COVID-19 treatment [ 129 ].…”

Section: Nucleoside Analogs As Anti-hcov Drugsmentioning

confidence: 99%

Nucleoside Analogs and Nucleoside Precursors as Drugs in the Fight against SARS-CoV-2 and Other Coronaviruses

et al. 2021

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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.

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Section: Nucleoside Analogs As Anti-hcov Drugsmentioning

confidence: 99%

Nucleoside Analogs and Nucleoside Precursors as Drugs in the Fight against SARS-CoV-2 and Other Coronaviruses

et al. 2021

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“…COVID-19 is caused by a novel coronavirus, designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an enveloped positive single-strand RNA virus [1]. Although COVID-19 vaccines are now in deployment, eradication is unrealistic and there is an unmet parallel need for effective SARS-CoV-2 antivirals [2,3] to inhibit active virus replication in patients to reverse virus progression. Given that not all vaccines will necessarily prevent virus shedding in subsequent infection, antivirals could also serve to reduce the overall virus levels circulating in a population, thus reducing its spread.…”

Section: Introductionmentioning

confidence: 99%

Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus

Al-Beltagi

Preda

Goulding

et al. 2021

Viruses

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The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to include antivirals to treat acute infections, in addition to the judicious use of effective vaccines. Whilst COVID-19 vaccines are being rolled out for mass vaccination, the modest number of antivirals in use or development for any disease bears testament to the challenges of antiviral development. We recently showed that non-cytotoxic levels of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase pump, induces a potent host innate immune antiviral response that blocks influenza A virus replication. Here we show that TG is also highly effective in blocking the replication of respiratory syncytial virus (RSV), common cold coronavirus OC43, SARS-CoV-2 and influenza A virus in immortalized or primary human cells. TG’s antiviral performance was significantly better than remdesivir and ribavirin in their respective inhibition of OC43 and RSV. Notably, TG was just as inhibitory to coronaviruses (OC43 and SARS-CoV-2) and influenza viruses (USSR H1N1 and pdm 2009 H1N1) in separate infections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against a lethal influenza virus challenge. Together with its ability to inhibit the different viruses before or during active infection, and with an antiviral duration of at least 48 h post-TG exposure, we propose that TG (or its derivatives) is a promising broad-spectrum inhibitor against SARS-CoV-2, OC43, RSV and influenza virus.

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“…In this investigation, we performed a blind docking approach, followed by molecular dynamics (MD) simulation coupled with binding free energy techniques that dissect the structural dynamics and energy basis of molecular recognition [ 41 , 42 ]. The MPD3 phytochemical database [ 43 ] along with a pool of natural antiviral compounds were used against multiple SARS-CoV-2 protein targets to understand their binding mechanism and put forward a hypothesis on how to further optimize these structures to enhance selectivity and maximize anti-SARS-CoV-2 biological potency [ 44 , 45 , 46 , 47 ]. A schematic summary of the methodology used in this work is provided in Figure 1 .…”

Section: Introductionmentioning

confidence: 99%

Computational Determination of Potential Multiprotein Targeting Natural Compounds for Rational Drug Design Against SARS-COV-2

et al. 2021

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SARS-CoV-2 caused the current COVID-19 pandemic and there is an urgent need to explore effective therapeutics that can inhibit enzymes that are imperative in virus reproduction. To this end, we computationally investigated the MPD3 phytochemical database along with the pool of reported natural antiviral compounds with potential to be used as anti-SARS-CoV-2. The docking results demonstrated glycyrrhizin followed by azadirachtanin, mycophenolic acid, kushenol-w and 6-azauridine, as potential candidates. Glycyrrhizin depicted very stable binding mode to the active pocket of the Mpro (binding energy, −8.7 kcal/mol), PLpro (binding energy, −7.9 kcal/mol), and Nucleocapsid (binding energy, −7.9 kcal/mol) enzymes. This compound showed binding with several key residues that are critical to natural substrate binding and functionality to all the receptors. To test docking prediction, the compound with each receptor was subjected to molecular dynamics simulation to characterize the molecule stability and decipher its possible mechanism of binding. Each complex concludes that the receptor dynamics are stable (Mpro (mean RMSD, 0.93 Å), PLpro (mean RMSD, 0.96 Å), and Nucleocapsid (mean RMSD, 3.48 Å)). Moreover, binding free energy analyses such as MMGB/PBSA and WaterSwap were run over selected trajectory snapshots to affirm intermolecular affinity in the complexes. Glycyrrhizin was rescored to form strong affinity complexes with the virus enzymes: Mpro (MMGBSA, −24.42 kcal/mol and MMPBSA, −10.80 kcal/mol), PLpro (MMGBSA, −48.69 kcal/mol and MMPBSA, −38.17 kcal/mol) and Nucleocapsid (MMGBSA, −30.05 kcal/mol and MMPBSA, −25.95 kcal/mol), were dominated mainly by vigorous van der Waals energy. Further affirmation was achieved by WaterSwap absolute binding free energy that concluded all the complexes in good equilibrium and stability (Mpro (mean, −22.44 kcal/mol), PLpro (mean, −25.46 kcal/mol), and Nucleocapsid (mean, −23.30 kcal/mol)). These promising findings substantially advance our understanding of how natural compounds could be shaped to counter SARS-CoV-2 infection.

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Antivirals Against Coronaviruses: Candidate Drugs for SARS-CoV-2 Treatment?

Cited by 91 publications

References 246 publications

Nucleoside Analogs and Nucleoside Precursors as Drugs in the Fight against SARS-CoV-2 and Other Coronaviruses

Nucleoside Analogs and Nucleoside Precursors as Drugs in the Fight against SARS-CoV-2 and Other Coronaviruses

Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus

Computational Determination of Potential Multiprotein Targeting Natural Compounds for Rational Drug Design Against SARS-COV-2

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