Characterization of Critical Determinants of ACE2–SARS CoV-2 RBD Interaction

Brown, Emily E.F.; Rezaei, Reza; Jamieson, Taylor; Dave, Jaahnavi; Martin, Nikolas T.; Singaravelu, Ragunath; Crupi, Mathieu J.F.; Boulton, Stephen; Tucker, Sarah J.; Duong, Jessie; Poutou, Joanna; Pelin, Adrian; Yasavoli‐Sharahi, Hamed; Taha, Zaid; Arulanandam, Rozanne; Surendran, Abera; Ghahremani, Mina; Austin, Bradley; Matar, Chantal; Diallo, Jean-Simon; Bell, John C.; Ilkow, Carolina S.; Azad, Taha

doi:10.3390/ijms22052268

Cited by 25 publications

(29 citation statements)

References 32 publications

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“…The nanoluciferase complementation assay has been previously described in refs. 24 , 25 We tested the impact of atovaquone on SARS binding to ACE2 using a variety of plasmid constructs, notably the RBD or S1 domain from SARS-CoV2 or the RBD domain from SARS-CoV1 as described. 24 , 25 Following plasmid transfection using a PolyJet transfection reagent (SignaGen Laboratories) in HEK293, cells were lysed in a NanoLuc-compatible passive lysis buffer (Promega) and the lysate was dispensed into a 384-well plate to which atovaquone was added at a final concentration of 4 μM.…”

Section: Methodsmentioning

confidence: 99%

Antiviral Potential of the Antimicrobial Drug Atovaquone against SARS-CoV-2 and Emerging Variants of Concern

et al. 2021

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The antimicrobial medication malarone (atovaquone/proguanil) is used as a fixed-dose combination for treating children and adults with uncomplicated malaria or as chemoprophylaxis for preventing malaria in travelers. It is an inexpensive, efficacious, and safe drug frequently prescribed around the world. Following anecdotal evidence from 17 patients in the provinces of Quebec and Ontario, Canada, suggesting that malarone/atovaquone may present some benefits in protecting against COVID-19, we sought to examine its antiviral potential in limiting the replication of SARS-CoV-2 in cellular models of infection. In VeroE6 expressing human TMPRSS2 and human lung Calu-3 epithelial cells, we show that the active compound atovaquone at micromolar concentrations potently inhibits the replication of SARS-CoV-2 and other variants of concern including the alpha, beta, and delta variants. Importantly, atovaquone retained its full antiviral activity in a primary human airway epithelium cell culture model. Mechanistically, we demonstrate that the atovaquone antiviral activity against SARS-CoV-2 is partially dependent on the expression of TMPRSS2 and that the drug can disrupt the interaction of the spike protein with the viral receptor, ACE2. Additionally, spike-mediated membrane fusion was also reduced in the presence of atovaquone. In the United States, two clinical trials of atovaquone administered alone or in combination with azithromycin were initiated in 2020. While we await the results of these trials, our findings in cellular infection models demonstrate that atovaquone is a potent antiviral FDA-approved drug against SARS-CoV-2 and other variants of concern in vitro.

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Section: Methodsmentioning

confidence: 99%

Antiviral Potential of the Antimicrobial Drug Atovaquone against SARS-CoV-2 and Emerging Variants of Concern

et al. 2021

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“…We found that there were slight differences of the neutralizing activity among the three groups (RBD/hACE2, RBD/Non-hACE2, and Non-RBD) of spike mutants but were insignificant (Figure 4). It was accepted that the mutations located in the RBD/hACE2 region more likely alter the viral neutralization reactivity to antibodies (20). Our results of the neutralization of the convalescent plasma against different spike variants indicated that mutations in either RBD/hACE2 or RBD/Non-hACE2 interaction regions slightly decreased the neutralizing activity of the convalescent plasma against the corresponding pseudoviruses.…”

Section: Discussionmentioning

confidence: 63%

Crucial Mutations of Spike Protein on SARS-CoV-2 Evolved to Variant Strains Escaping Neutralization of Convalescent Plasmas and RBD-Specific Monoclonal Antibodies

Ding

Zhang

et al. 2021

Front. Immunol.

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Small number of SARS-CoV-2 epidemic lineages did not efficiently exhibit a neutralization profile, while single amino acid mutation in the spike protein has not been confirmed in altering viral antigenicity resulting in immune escape. To identify crucial mutations in spike protein that escape humoral immune response, we evaluated the cross-neutralization of convalescent plasmas and RBD-specific monoclonal antibodies (mAbs) against various spike protein-based pseudoviruses. Three of 24 SARS-CoV-2 pseudoviruses containing different mutations in spike protein, including D614G, A475V, and E484Q, consistently showed an altered sensitivity to neutralization by convalescent plasmas. A475V and E484Q mutants are highly resistant to neutralization by mAb B38 and 2-4, suggesting that some crucial mutations in spike protein might evolve SARS-CoV-2 variants capable of escaping humoral immune response.

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“…We also used a concatenated alignment with four ACE2 regions containing residues involved in binding to S protein of SARS-CoV-2 (Supplementary file 1 ). ACE2 binding regions that encompass the key residues enabling interactions with SARS-CoV-2 S protein were based on previous studies (Shang et al 2020 ; Brown et al 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Prediction of SARS-CoV-2 hosts among Brazilian mammals and new coronavirus transmission chain using evolutionary bioinformatics

et al. 2021

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Severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 are thought to transmit to humans via wild mammals, especially bats. However, evidence for direct bat-to-human transmission is lacking. Involvement of intermediate hosts is considered a reason for SARS-CoV-2 transmission to humans and emergence of outbreak. Large biodiversity is found in tropical territories, such as Brazil. On the similar line, this study aimed to predict potential coronavirus hosts among Brazilian wild mammals based on angiotensin-converting enzyme 2 (ACE2) sequences using evolutionary bioinformatics. Cougar, maned wolf, and bush dogs were predicted as potential hosts for coronavirus. These indigenous carnivores are philogenetically closer to the known SARS-CoV/SARS-CoV-2 hosts and presented low ACE2 divergence. A new coronavirus transmission chain was developed in which white-tailed deer, a susceptible SARS-CoV-2 host, have the central position. Cougar play an important role because of its low divergent ACE2 level in deer and humans. The discovery of these potential coronavirus hosts will be useful for epidemiological surveillance and discovery of interventions that can contribute to break the transmission chain.

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Characterization of Critical Determinants of ACE2–SARS CoV-2 RBD Interaction

Cited by 25 publications

References 32 publications

Antiviral Potential of the Antimicrobial Drug Atovaquone against SARS-CoV-2 and Emerging Variants of Concern

Antiviral Potential of the Antimicrobial Drug Atovaquone against SARS-CoV-2 and Emerging Variants of Concern

Crucial Mutations of Spike Protein on SARS-CoV-2 Evolved to Variant Strains Escaping Neutralization of Convalescent Plasmas and RBD-Specific Monoclonal Antibodies

Prediction of SARS-CoV-2 hosts among Brazilian mammals and new coronavirus transmission chain using evolutionary bioinformatics

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