A robust SARS-CoV-2 replication model in primary human epithelial cells at the air liquid interface to assess antiviral agents

Dan, Thuc Nguyen; Donckers, Kim; Vangeel, Laura; Chatterjee, Arnab K.; Gallay, Philippe; Bobardt, Michael; Bilello, John P.; Cihlář, Tomáš; Jonghe, Steven De; Neyts, Johan; Jochmans, Dirk

doi:10.1016/j.antiviral.2021.105122

Cited by 50 publications

(30 citation statements)

References 43 publications

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“…Of note, recent studies reported no anti-SARS-CoV-2 activities for AT-511 in a variety of cell models, including Vero, Huh7, and human respiratory epithelial cells. The author suggests that differences between models may contribute to differences in the metabolism of AT-511 into the active form, thus compromising its antiviral activity (Do et al, 2021). Since AT-511 is a double prodrug requiring multiple enzymes for activation, it may be more susceptible to different experimental conditions (Do et al, 2021).…”

Section: Inhibitors Of Sars-cov-2 Rdrpmentioning

confidence: 99%

Mechanism of Action of Small-Molecule Agents in Ongoing Clinical Trials for SARS-CoV-2: A Review

Zhao¹,

Li²,

Zhong³

2022

Front. Pharmacol.

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Since the first reports from December 2019, COVID-19 caused an overwhelming global pandemic that has affected 223 countries, seriously endangering public health and creating an urgent need for effective drugs to treat SARS-CoV-2 infection. Currently, there is a lack of safe, effective, and specific therapeutic drugs for COVID-19, with mainly supportive and symptomatic treatments being administered to patients. The preferred option for responding to an outbreak of acute infectious disease is through drug repurposing, saving valuable time that would otherwise be lost in preclinical and clinical research, hastening clinical introduction, and lowering treatment costs. Alternatively, researchers seek to design and discover novel small-molecule candidate drugs targeting the key proteins in the life cycle of SARS-CoV-2 through an in-depth study of the infection mechanism, thus obtaining a number of candidate compounds with favorable antiviral effects in preclinical and clinical settings. There is an urgent need to further elucidate the efficacy and mechanism of action of potential anti-SARS-CoV-2 small-molecule drugs. Herein, we review the candidate small-molecule anti-SARS-CoV-2 drugs in ongoing clinical trials, with a major focus on their mechanisms of action in an attempt to provide useful insight for further research and development of small-molecule compounds against SARS-CoV-2 infection.

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Section: Inhibitors Of Sars-cov-2 Rdrpmentioning

confidence: 99%

Mechanism of Action of Small-Molecule Agents in Ongoing Clinical Trials for SARS-CoV-2: A Review

Zhao¹,

Li²,

Zhong³

2022

Front. Pharmacol.

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“…In the presence of an antiviral compound, the cytopathogenicity is inhibited and the fluorescent signal maintained. To this end VeroE6-GFP cells (kindly provided by Marnix Van Loock, Janssen Pharmaceutica, Beerse, Belgium), were used as described previously ( Do et al, 2021 ; Rana Abdelnabi et al, 2021 ). Since VeroE6 cells show a high efflux of some chemotypes, the antiviral assays were performed in the presence of the P-glycoprotein (Pgp) efflux inhibitor CP-100356 (0.5 μM)( Hoffman et al, 2020 ).…”

mentioning

confidence: 99%

Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern

et al. 2022

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We assessed the in vitro antiviral activity of remdesivir and its parent nucleoside GS-441524, molnupiravir and its parent nucleoside EIDD-1931 and the viral protease inhibitor nirmatrelvir against the ancestral SARS-CoV2 strain and the five variants of concern including Omicron. VeroE6-GFP cells were pre-treated overnight with serial dilutions of the compounds before infection. The GFP signal was determined by high-content imaging on day 4 post-infection. All molecules have equipotent antiviral activity against the ancestral virus and the VOCs Alpha, Beta, Gamma, Delta and Omicron. These findings are in line with the observation that the target proteins of these antivirals (respectively the viral RNA dependent RNA polymerase and the viral main protease Mpro) are highly conserved.

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“…Since the beginning of pandemic, WHO declared 5 of these variants as VOCs that could be associated with more severe disease and/or increased rate of transmission. While the SARS-CoV-2 antiviral activity of RDV has previously been well characterized both in vitro and in vivo (13, 24, 26, 29–31), most studies have been conducted using the ancestral WA1 isolate. Here, we sought to fully characterize the antiviral potency of RDV and its parent nucleoside GS-441524 against a panel of the most significant SARS-CoV-2 variants including all the major VOCs.…”

Section: Resultsmentioning

confidence: 99%

Remdesivir and GS-441524 retain antiviral activity against Delta, Omicron, and other emergent SARS-CoV-2 variants

Pitts

Perry

et al. 2022

Preprint

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Genetic variation of SARS-CoV-2 has resulted in the emergence and rapid spread of multiple variants throughout the pandemic, of which Omicron is currently the predominant variant circulating worldwide. SARS-CoV-2 variants of concern or interest (VOC/VOI) have evidence of increased viral transmission, disease severity, or decreased effectiveness of vaccines and neutralizing antibodies. Remdesivir (RDV, VEKLURY®) is a nucleoside analog prodrug and the first FDA-approved antiviral treatment of COVID-19. Here we present a comprehensive antiviral activity assessment of RDV and its parent nucleoside, GS-441524, against 10 current and former SARS-CoV-2 VOC/VOI clinical isolates by nucleoprotein ELISA and plaque reduction assay. Delta and Omicron variants remained susceptible to RDV and GS-441524, with EC50 values 0.31 to 0.62-fold of those observed against the ancestral WA1 isolate. All other tested variants exhibited EC50 values ranging from 0.15 to 2.3-fold of the observed EC50 values against WA1. Analysis of nearly 6 million publicly available variant isolate sequences confirmed that Nsp12, the RNA-dependent RNA polymerase (RdRp) target of RDV and GS-441524, is highly conserved across variants with only 2 prevalent changes (P323L and G671S). Using recombinant viruses, both RDV and GS-441524 retained potency against all viruses containing frequent variant substitutions or their combination. Taken together, these results highlight the conserved nature of SARS-CoV-2 Nsp12 and provide evidence of sustained SARS-CoV-2 antiviral activity of RDV and GS-441524 across the tested variants. The observed pan-variant activity of RDV supports its continued use for the treatment of COVID-19 regardless of the SARS-CoV-2 variant.

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A robust SARS-CoV-2 replication model in primary human epithelial cells at the air liquid interface to assess antiviral agents

Cited by 50 publications

References 43 publications

Mechanism of Action of Small-Molecule Agents in Ongoing Clinical Trials for SARS-CoV-2: A Review

Mechanism of Action of Small-Molecule Agents in Ongoing Clinical Trials for SARS-CoV-2: A Review

Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern

Remdesivir and GS-441524 retain antiviral activity against Delta, Omicron, and other emergent SARS-CoV-2 variants

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