The Host Cell ViroCheckpoint: Identification and Pharmacologic Targeting of Novel Mechanistic Determinants of Coronavirus-Mediated Hijacked Cell States
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Abstract
Most antiviral agents are designed to target virus-specific proteins and mechanisms rather than the host cell proteins that are critically dysregulated following virus-mediated reprogramming of the host cell transcriptional state. To overcome these limitations, we propose that elucidation and pharmacologic targeting of host cell Master Regulator proteins—whose aberrant activities govern the reprogramed state of infected-coronavirus cells—presents unique opportunities to develop novel mechanism-based therapeutic approaches to antiviral therapy, either as monotherapy or as a complement to established treatments. Specifically, we propose that a small module of host cell Master Regulator proteins (ViroCheckpoint) is hijacked by the virus to support its efficient replication and release. Conventional methodologies are not well suited to elucidate these potentially targetable proteins. By using the VIPER network-based algorithm, we successfully interrogated 12h, 24h, and 48h signatures from Calu-3 lung adenocarcinoma cells infected with SARS-CoV, to elucidate the time-dependent reprogramming of host cells and associated Master Regulator proteins. We used the NYS CLIA-certified Darwin OncoTreat algorithm, with an existing database of RNASeq profiles following cell perturbation with 133 FDA-approved and 195 late-stage experimental compounds, to identify drugs capable of virtually abrogating the virus-induced Master Regulator signature. This approach to drug prioritization and repurposing can be trivially extended to other viral pathogens, including SARS-CoV-2, as soon as the relevant infection signature becomes available.
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SciScore for 10.1101/2020.05.12.091256: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources NCI-H1793 cells, plated in 384-well plates, were then perturbed with a library of 328 FDA-approved drugs and small-molecule compounds at their corresponding ED20 concentration. NCI-H1793suggested: ATCC Cat# CRL-5896, RRID:CVCL_1496)Software and Algorithms Sentences Resources RNA-Seq reads were mapped to the human reference genome assembly 38 using the STAR aligner(81). STARsuggested: (STAR, RRID:SCR_015899)Expression data were then … SciScore for 10.1101/2020.05.12.091256: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources NCI-H1793 cells, plated in 384-well plates, were then perturbed with a library of 328 FDA-approved drugs and small-molecule compounds at their corresponding ED20 concentration. NCI-H1793suggested: ATCC Cat# CRL-5896, RRID:CVCL_1496)Software and Algorithms Sentences Resources RNA-Seq reads were mapped to the human reference genome assembly 38 using the STAR aligner(81). STARsuggested: (STAR, RRID:SCR_015899)Expression data were then normalized by equivariance transformation, based on the negative binomial distribution with the DESeq R-system package (Bioconductor(82)). DESeqsuggested: (DESeq, RRID:SCR_000154)Differential gene expression signatures were computed by comparing each condition with plate-matched vehicle control samples using a moderated Student’s t-test as implemented in the limma package from Bioconductor(83). limmasuggested: (LIMMA, RRID:SCR_010943)Individual gene expression signatures were then transformed into protein activity signatures with the VIPER algorithm(37), based on the a lung adenocarcinoma context-specific regulatory network available from the aracne.networks package from Bioconductor. Bioconductorsuggested: (Bioconductor, RRID:SCR_006442)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:This analysis has several limitations that partially restrict its value as proof of concept. Specifically, infection was conducted in a cancer cell line, rather than in a more physiologically relevant context, such as in primary bronchial or alveolar epithelial cells. In addition, drug perturbations were also performed in a cancer cell line context, thus potentially introducing undesired confounding factors, even though use of mock controls for the infection, and vehicle control for the drug perturbations, from the same cancer cell line should have eliminated most of the cancer-related bias and cell line idiosyncrasies. As a result, extrapolation of this approach to the clinic may be limited by the following assumptions: (a) that the host cell regulatory checkpoint hijacked by the virus is conserved between the Calu-3 adenocarcinoma cell line and the normal alveolar or bronchial epithelial cells in vivo; and (2) that the drugs’ and compounds’ MoA is conserved between the NCI-H1793 lung adenocarcinoma cells and normal lung epithelial cells in vivo. Moreover, while for the generation of the perturbational data and the context-specific MoA database we used subtoxic drug concentrations that, in most cases, were well below the maximum tolerated dose for all drugs and compounds, the relevant pharmacologic concentration for their deployment as antiviral therapy may be much lower than the original recommended concentration for their use as anti-cancer drugs. Further research is neces...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04355676 Withdrawn Evaluation of Activity and Safety of Two Regimens of Low Dos… NCT04349098 Completed Evaluation of Activity and Safety of Oral Selinexor in Parti… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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