Thiol drugs decrease SARS-CoV-2 lung injury<i>in vivo</i>and disrupt SARS-CoV-2 spike complex binding to ACE2<i>in vitro</i>

Khanna, Kritika; Raymond, Wilfred W.; Charbit, Annabelle R; Jin, Jong-Sik; Gitlin, Irina; Tang, Monica; Sperber, Hannah Sabeth; Franz, Sergej; Pillai, Satish K.; Simmons, Graham; Fahy, John V.

doi:10.1101/2020.12.08.415505

Cited by 27 publications

(27 citation statements)

References 76 publications

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“…Instead, L452, together with F490 and L492, form a hydrophobic patch on the surface of the spike RBD (Figure 4A). To understand the effects of L452R RBD mutation on viral entry, pseudoviruses carrying D614G with L452R or W152C, or D614G alone were generated and used for infection of 293T cells stably expressing the ACE2 cell entry receptor and TMPRSS2 cofactor for SARS-CoV-2 (Hoffmann et al, 2020;Khanna et al, 2020). We See also Tables S1 and S5.…”

Section: Increased Transmissibility and Infectivitymentioning

confidence: 99%

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Transmission, infectivity, and neutralization of a spike L452R SARS-CoV-2 variant

Deng

Garcia-Knight

Khalid

et al. 2021

Cell

488

354

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We identified an emerging SARS-CoV-2 variant by viral whole-genome sequencing of 2,172 nasal/nasopharyngeal swab samples from 44 counties in California, a state in the Western United States. Named B.1.427/B.1.429 to denote its 2 lineages, the variant emerged in May 2020 and increased from 0% to >50% of sequenced cases from September 2020 to January 2021, showing 18.6-24% increased transmissibility relative to wild-type circulating strains. The variant carries 3 mutations in the spike protein, including an L452R substitution. We found 2-fold increased B.1.427/B.1.429 viral shedding in vivo and increased L452R pseudovirus infection of cell cultures and lung organoids, albeit decreased relative to pseudoviruses carrying the N501Y mutation common to variants B.1.1.7, B.1.351, and P.1. Antibody neutralization assays revealed 4.0 to 6.7-fold and 2.0-fold decreases in neutralizing titers from convalescent patients and vaccine recipients, respectively. The increased prevalence of a more transmissible variant in California exhibiting decreased antibody neutralization warrants further investigation.

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Section: Increased Transmissibility and Infectivitymentioning

confidence: 99%

“…Cells used for this study include Vero E6 cells, Vero-81 cells, Vero cells overexpressing human TMPRSS2 (Vero-TMPRSS2), A549 cells stably expressing ACE2 (A549-ACE2), and 293T cells stably expressing ACE2 and TMPRSS2 (293T-ACE2-TMPRSS2) (Khanna et al, 2020).…”

Section: Cell Culture Modelsmentioning

confidence: 99%

Transmission, infectivity, and neutralization of a spike L452R SARS-CoV-2 variant

Deng

Garcia-Knight

Khalid

et al. 2021

Cell

488

354

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“…Other mechanisms could be involved in a potential beneficial effect of dalcetrapib in the prevention of SARS-CoV-2 infection. Indeed, two cysteine residues, Cys480 and Cys488, of the viral spike protein have been recently shown to be important for the binding of the spike protein to the ACE2 receptor, 32 and thiol-reactive substances including dalcetrapib (JTT-705) have shown to inhibit this important interaction and prevent syncytia formation and viral entry into cells. 33 Hati and Bhattacharyya 34 showed that the redox status plays an important role in the stability of key disulfide bonds present in both the spike protein and the ACE2 receptor.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the 3CL Protease and SARS-CoV-2 Replication by Dalcetrapib

Niesor¹,

Boivin

Rhéaume

et al. 2021

ACS Omega

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The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) 3CL protease is a promising target for inhibition of viral replication by interaction with a cysteine residue (Cys145) at its catalytic site. Dalcetrapib exerts its lipid-modulating effect by binding covalently to cysteine 13 of a cholesteryl ester transfer protein. Because 12 free cysteine residues are present in the 3CL protease, we investigated the potential of dalcetrapib to inhibit 3CL protease activity and SARS-CoV-2 replication. Molecular docking investigations suggested that dalcetrapib-thiol binds to the catalytic site of the 3CL protease with a delta G value of −8.5 kcal/mol. Dalcetrapib inhibited both 3CL protease activity in vitro and viral replication in Vero E6 cells with IC 50 values of 14.4 ± 3.3 μM and an EC 50 of 17.5 ± 3.5 μM (mean ± SD). Near-complete inhibition of protease activity persisted despite 1000-fold dilution after ultrafiltration with a nominal dalcetrapib-thiol concentration of approximately 100 times below the IC 50 of 14.4 μM, suggesting stable protease–drug interaction. The inhibitory effect of dalcetrapib on the SARS-CoV-2 3CL protease and viral replication warrants its clinical evaluation for the treatment of COVID-19.

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“…Polyclonal cell populations were selected via fluorescence-activated cell sorting (FACS) as described below. The HEK293T cell line expressing ACE2 and TM-PRSS2 was generated as previously described 57 .…”

Section: Generation Of Stable Cell Linesmentioning

confidence: 99%

Sentinel cells enable genetic detection of SARS-CoV-2 Spike protein

Weinberg¹,

Hilburger

Kim³

et al. 2021

Preprint

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The COVID-19 pandemic has demonstrated the need for exploring different diagnostic and therapeutic modalities to tackle future viral threats. In this vein, we propose the idea of sentinel cells, cellular biosensors capable of detecting viral antigens and responding to them with customizable responses. Using SARS-CoV-2 as a test case, we developed a live cell sensor (SARSNotch) using a de novo-designed protein binder against the SARS-CoV-2 Spike protein. SARSNotch is capable of driving custom genetically-encoded payloads in immortalized cell lines or in primary T lymphocytes in response to purified SARS-CoV-2 Spike or in the presence of Spike-expressing cells. Furthermore, SARSNotch is functional in a cellular system used in directed evolution platforms for development of better binders or therapeutics. In keeping with the rapid dissemination of scientific knowledge that has characterized the incredible scientific response to the ongoing pandemic, we extend an open invitation for others to make use of and improve SARSNotch sentinel cells in the hopes of unlocking the potential of the next generation of smart antiviral therapeutics.

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Thiol drugs decrease SARS-CoV-2 lung injuryin vivoand disrupt SARS-CoV-2 spike complex binding to ACE2in vitro

Cited by 27 publications

References 76 publications

Transmission, infectivity, and neutralization of a spike L452R SARS-CoV-2 variant

Transmission, infectivity, and neutralization of a spike L452R SARS-CoV-2 variant

Inhibition of the 3CL Protease and SARS-CoV-2 Replication by Dalcetrapib

Sentinel cells enable genetic detection of SARS-CoV-2 Spike protein

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