A cell-based assay to discover inhibitors of SARS-CoV-2 RNA dependent RNA polymerase

Zhao, Jin; Guo, Shuang; Yi, Dongrong; Li, Quanjie; Ma, Ling; Zhang, Yongxin; Wang, Jing; Li, Xiaoyü; Guo, Fei; Lin, Rongtuan; Liang, Chen; Liu, Zhenlong; Cen, Shan

doi:10.1016/j.antiviral.2021.105078

Cited by 71 publications

(159 citation statements)

References 34 publications

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“…In the previous study, we developed a cell-based SARS-CoV-2 RdRp report system which can be deployed to discover SARS-CoV-2 RdRp inhibitors. 27 The system was composed of two parts: a Gluc reporter plasmid and the plasmids for expressing SARS-CoV-2 RdRp which is basically composed of nsp7, nsp8, and nsp12. The Gluc gene was under a tetracycline regulated expression promoter and flanked by 5′ and 3′ untranslated regions (UTRs) of SARS-CoV-2.…”

Section: Resultsmentioning

confidence: 99%

Quinoline and Quinazoline Derivatives Inhibit Viral RNA Synthesis by SARS-CoV-2 RdRp

et al. 2021

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Coronavirus disease 2019 (COVID-19) is a fatal respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The identification of potential drugs is urgently needed to control the pandemic. RNA dependent RNA polymerase (RdRp) is a conserved protein within RNA viruses and plays a crucial role in the viral life cycle, thus making it an attractive target for development of antiviral drugs. In this study, 101 quinoline and quinazoline derivatives were screened against SARS-CoV-2 RdRp using a cell-based assay. Three compounds I-13e , I-13h , and I-13i exhibit remarkable potency in inhibiting RNA synthesis driven by SARS-CoV-2 RdRp and relatively low cytotoxicity. Among these three compounds, I-13e showed the strongest inhibition upon RNA synthesis driven by SARS-CoV-2 RdRp, the resistance to viral exoribonuclease activity and the inhibitory effect on the replication of CoV, thus holding potential of being drug candidate for treatment of SARS-CoV-2.

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Section: Resultsmentioning

confidence: 99%

Quinoline and Quinazoline Derivatives Inhibit Viral RNA Synthesis by SARS-CoV-2 RdRp

et al. 2021

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“…In addition, the chemoinformatic analyses may not necessarily identify true ligand–protein interactions, and therefore crystallography studies or antibody neutralization studies could provide evidence of such interactions. In addition, although the lung organoid model provides a powerful systems-level approach to screen for compounds with putative protective effects against SARS-CoV-2, it models only the entry step of the SARS-CoV-2 replication cycle, and additional models could be useful to test the efficacy of specific drugs against other steps of the viral cycle (e.g., using a SARS-CoV-2 protease reporter (Froggatt et al 2020 ), or an RNA dependent RNA polymerase reporter (Zhao et al 2021 ). Finally, while we observed that atorvastatin inhibited viral entry in the lung organoid model, the observed IC50 was quite high.…”

Section: Discussionmentioning

confidence: 99%

“…When identifying compounds with prophylactic and treatment potential for viral infections, there are chemoinformatic methods that predict which drugs may bind to viral enzymes playing crucial roles in virus replication, such as the main protease (Mpro) or the RNA-dependent RNA polymerase (RdRp), potentially blocking their function (Singh et al 2020 ). In addition, it is possible to investigate whether specific drugs are likely to work in biological systems by testing their ability to block parts of the viral cycle in in vitro models of infection (Han et al 2020 ; Froggatt et al 2020 ; Zhao et al 2021 ). For example, Han et al ( 2020 ) generated a sophisticated COVID-19 lung organoid model utilizing SARS-CoV-2-Spike pseudovirus particles, to screen for compounds that could block viral entry.…”

Section: Introductionmentioning

confidence: 99%

Identifying FDA-approved drugs with multimodal properties against COVID-19 using a data-driven approach and a lung organoid model of SARS-CoV-2 entry

Duarte

Copertino

Íñiguez

et al. 2021

Mol Med

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Background Vaccination programs have been launched worldwide to halt the spread of COVID-19. However, the identification of existing, safe compounds with combined treatment and prophylactic properties would be beneficial to individuals who are waiting to be vaccinated, particularly in less economically developed countries, where vaccine availability may be initially limited. Methods We used a data-driven approach, combining results from the screening of a large transcriptomic database (L1000) and molecular docking analyses, with in vitro tests using a lung organoid model of SARS-CoV-2 entry, to identify drugs with putative multimodal properties against COVID-19. Results Out of thousands of FDA-approved drugs considered, we observed that atorvastatin was the most promising candidate, as its effects negatively correlated with the transcriptional changes associated with infection. Atorvastatin was further predicted to bind to SARS-CoV-2’s main protease and RNA-dependent RNA polymerase, and was shown to inhibit viral entry in our lung organoid model. Conclusions Small clinical studies reported that general statin use, and specifically, atorvastatin use, are associated with protective effects against COVID-19. Our study corroborrates these findings and supports the investigation of atorvastatin in larger clinical studies. Ultimately, our framework demonstrates one promising way to fast-track the identification of compounds for COVID-19, which could similarly be applied when tackling future pandemics.

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“…As previously addressed, RdRp is one of the most promising targets for the development of anti-SARS-CoV-2 therapeutics. Aside from playing a crucial role in viral RNA synthesis, RdRp lacks cellular homologues and is highly conserved in terms of sequence and structure among coronaviruses ( Chien et al, 2020 ; Hillen et al, 2020 ; Aftab et al, 2020 ; Shyr et al, 2020 ; Zhao et al, 2021a ). As previously shown, RdRp complex is comprised of catalytic subunit nsp12, two accessory subunits nsp7 and nsp8, and RNA template-product duplex( Hillen et al, 2020 ; Gao et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

2-((1H-indol-3-yl)thio)-N-phenyl-acetamides: SARS-CoV-2 RNA-dependent RNA polymerase inhibitors

Zhao

Zhang

et al. 2021

Antiviral Research

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A cell-based assay to discover inhibitors of SARS-CoV-2 RNA dependent RNA polymerase

Cited by 71 publications

References 34 publications

Quinoline and Quinazoline Derivatives Inhibit Viral RNA Synthesis by SARS-CoV-2 RdRp

Quinoline and Quinazoline Derivatives Inhibit Viral RNA Synthesis by SARS-CoV-2 RdRp

Identifying FDA-approved drugs with multimodal properties against COVID-19 using a data-driven approach and a lung organoid model of SARS-CoV-2 entry

2-((1H-indol-3-yl)thio)-N-phenyl-acetamides: SARS-CoV-2 RNA-dependent RNA polymerase inhibitors

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