One year update on the COVID-19 pandemic: Where are we now?

Mishra, Sanjay; Tripathi, Timir

doi:10.1016/j.actatropica.2020.105778

Cited by 176 publications

(173 citation statements)

References 164 publications

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“…The rapid availability of more SARS-CoV-2 genomes, most of which differ by one or few mutations, enables the accurate investigation into spread patterns. Genomic epidemiology-based analysis is being used to control the rapidly spreading SARS-CoV-2 outbreak ( Mishra and Tripathi, 2021 ). Combined with the availability of more genomic data, our information on mutation repertoires is critical for predicting structural features that may guide the design of new drugs to counter resistant strains.…”

Section: Discussionmentioning

confidence: 99%

High-throughput rational design of the remdesivir binding site in the RdRp of SARS-CoV-2: implications for potential resistance

et al. 2021

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The use of remdesivir to treat COVID-19 will likely continue before clinical trials are completed. Due to the lengthening pandemic and evolving nature of the virus, predicting potential residues prone to mutation is crucial for the management of remdesivir resistance. Using a rational ligand-based interface design complemented with mutational mapping, we generated a total of 100,000 mutations and provided insight into the functional outcomes of mutations in the remdesivir-binding site in nsp12 subunit of RdRp. After designing 46 residues in the remdesivir-binding site of nsp12, the designs retained 97%-98% sequence identity, suggesting that very few mutations in nsp12 are required for SARS-CoV-2 to attain remdesivir resistance. Several mutants displayed decreased binding affinity to remdesivir, suggesting drug resistance. These hotspot residues had a higher probability of undergoing selective mutation and thus conferring remdesivir resistance. Identifying the potential residues prone to mutation improves our understanding of SARS-CoV-2 drug resistance and COVID-19 pathogenesis.

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Section: Discussionmentioning

confidence: 99%

High-throughput rational design of the remdesivir binding site in the RdRp of SARS-CoV-2: implications for potential resistance

et al. 2021

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“…A closer inspection of interactions and energy components revealed that the hydrogen bonds and van der Waals pairs contributing to the hydrogen bond and van der Waals energies largely governed the difference in the total stabilizing energy and between the affinity of the RBD/ACE2 complex in its apo-RBD/ACE2 and RBD/ACE2-arbidol complexes ( Table 3 ). ( Mishra and Tripathi, 2021 ) ( Wang et al, 2020e ) ( The, 2020 )…”

Section: Resultsmentioning

confidence: 99%

Unraveling the mechanism of arbidol binding and inhibition of SARS-CoV-2: Insights from atomistic simulations

Padhi

Seal

Khan

et al. 2021

European Journal of Pharmacology

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The COVID-19 pandemic has spread rapidly and posed an unprecedented threat to the global economy and human health. Broad-spectrum antivirals are currently being administered to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). China's prevention and treatment guidelines suggest the use of an antiinfluenza drug, arbidol, for the clinical treatment of COVID-19. Reports indicate that arbidol could neutralize SARS-CoV-2. Monotherapy with arbidol is found to be superior to lopinavir-ritonavir or favipiravir for treating COVID-19. In SARS-CoV-2 infection, arbidol acts by interfering with viral binding to the host cells. However, the detailed mechanism through which arbidol induces the inhibition of SARS-CoV-2 is not known. Here, we present atomistic insights into the mechanism underlying membrane fusion inhibition by arbidol for SARS-CoV-2. Molecular dynamics (MD) simulation-based analyses demonstrate that arbidol binds and stabilizes at the receptor-binding domain (RBD)/ACE2 interface with a high affinity. It forms stronger intermolecular interactions with the RBD than ACE2. Analyses of the detailed decomposition of energy components and binding affinities revealed a substantial increase in the affinity between the RBD and ACE2 in the arbidol-bound RBD/ACE2 complex, suggesting that arbidol could generate favorable interactions between them. Based on our MD simulation results, we propose that the binding of arbidol induces structural rigidity in the viral glycoprotein, resulting in a restriction of the conformational rearrangements associated with membrane fusion and virus entry. Furthermore, key residues of the RBD and ACE2 that interact with arbidol were identified, opening the door for developing therapeutic strategies and higher-efficacy arbidol derivatives or lead drug candidates.

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“…In contrast to the above proteases, the neutrophil elastase is enriched in the nose of humans compared to other tissues ( 19 ) and neutrophils, a source for this elastase, are recruited to the nose in SARS-CoV-2 infection ( 20 ). Indeed, the now worldwide dominant Asp614Gly variant, introduced a new elastase proteolysis site in the spike protein ( 2, 21 ). Using ExPASy ( 22 ), we identified Thr716Ile and Ser982Ala in 501Y.V1 as potential new elastase cleavage sites (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Identified first in the second week of October, this variant became dominant in South Africa within a month. Six fixed substitutions in all the South African variants were identified (Table 1b): Asn501Tyr [identical to the 501Y.V1 UK variant ( 11 )] and Pro614Gly [identical to the European dominant variant, identified between March and April of 2020 ( 2 )], the Asp80Ala, Lys417Asn, Glu484Lys and Ala701Val. It appears that the combination of these substitutions results in increased infectivity without increasing COVID-19 severity ( 13 ).…”

Section: Main Textmentioning

confidence: 99%

“…When a mutation or set of mutations provide an advantage over the previous variants, the new variant becomes the dominant variant to spread. This is what occurred when the aspartate 614 in the spike protein of the initial (Wuhan) SARS-CoV-2 virus, mutated to a glycine (Asn614Gly); within a month, the new variant became the most dominant in Europe ( 2 ) and now globally ( 3 ). The Asn614Gly variant is associated with higher viral loads, but not with a more severe COVID-19 symptoms in infected individuals ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

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Increased elastase sensitivity and decreased intramolecular interactions in the more transmissible SARS-CoV-2 variants’ spike protein: Analysis of the new UK and SA SARS-CoV-2 variants

Pokhrel

Lee

Kraemer

et al. 2021

Preprint

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Two SARS-CoV-2 variants showing increased transmissibility relative to the Wuhan virus have recently been identified. Although neither variant causes more severe illness or increased risk of death, the faster spread of the virus is a major threat. Using computational tools, we found that the new SARS-CoV-2 variants may acquire an increased transmissibility by increasing the propensity of its spike protein to expose the receptor binding domain. This information leads to the identification of potential treatments to avert the imminent threat of these more transmittable SARS-CoV-2 variants.TeaserThe more infective SARS-CoV-2 variants may expose its Achilles Heel – an opportunity to reduce their spreading.

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One year update on the COVID-19 pandemic: Where are we now?

Cited by 176 publications

References 164 publications

High-throughput rational design of the remdesivir binding site in the RdRp of SARS-CoV-2: implications for potential resistance

High-throughput rational design of the remdesivir binding site in the RdRp of SARS-CoV-2: implications for potential resistance

Unraveling the mechanism of arbidol binding and inhibition of SARS-CoV-2: Insights from atomistic simulations

Increased elastase sensitivity and decreased intramolecular interactions in the more transmissible SARS-CoV-2 variants’ spike protein: Analysis of the new UK and SA SARS-CoV-2 variants

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