Identification of druggable host targets needed for SARS-CoV-2 infection by combined pharmacological evaluation and cellular network directed prioritization both in vitro and in vivo

Patten, J.J.; Keiser, Patrick T.; Gysi, Deisy Morselli; Menichetti, Giulia; Mori, Hiroyuki; Donahue, Callie J.; Gan, Xiao; Valle, Ítalo Faria do; Geoghegan-Barek, Kathleen; Anantpadma, Manu; Boytz, RuthMabel; Berrigan, Jacob; Hulsey-Stubbs, Sarah; Ayazika, Kirabo Tess; O’Leary, Colin; Jalloh, Sallieu; Wagner, Florence F.; Ayehunie, Seyoum; Elledge, Stephen J.; Anderson, Deborah; Loscalzo, Joseph; Žitnik, Marinka; Gummuluru, Suryaram; Namchuk, Mark; Barabási, Albert László; Davey, Robert A.

doi:10.1101/2021.04.20.440626

Cited by 6 publications

(5 citation statements)

References 66 publications

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“…1 A and B). To test the validity of the predictions, we identified 918 drugs ranked by all predictive pipelines, and experimentally screened them to identify those that inhibit viral infection and replication in cultured nonhuman primate cells (18); the successful outcomes were further validated in human-derived cells. We also collected clinical trial data to capture the medical community's collective assessment of drug candidates.…”

Section: Significancementioning

confidence: 99%

“…Each pipeline offers predictions for a different number of drugs that were frozen on April 15, 2020. We then identified 918 drugs for which all pipelines but P3 offered predictions, and experimentally validated their effect on the virus in VeroE6 cells (18). The experimental (E918, E74) and clinical trial lists C415 offered the ground truth for validation and rank aggregation.…”

Section: Experimental and Clinical Validation Of Drug-repurposing Pipelinesmentioning

confidence: 99%

“…Drugs with positive experimental outcomesList of the 77 drugs with a positive outcome (S&W) from in vitro screen(18). Drug response classification was obtained by a two-step model for drug response (SI Appendix, Section 4.3).…”

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confidence: 99%

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Network medicine framework for identifying drug-repurposing opportunities for COVID-19

Gysi

Valle

Žitnik

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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The COVID-19 pandemic has highlighted the need to quickly and reliably prioritize clinically approved compounds for their potential effectiveness for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Here, we deployed algorithms relying on artificial intelligence, network diffusion, and network proximity, tasking each of them to rank 6,340 drugs for their expected efficacy against SARS-CoV-2. To test the predictions, we used as ground truth 918 drugs experimentally screened in VeroE6 cells, as well as the list of drugs in clinical trials that capture the medical community’s assessment of drugs with potential COVID-19 efficacy. We find that no single predictive algorithm offers consistently reliable outcomes across all datasets and metrics. This outcome prompted us to develop a multimodal technology that fuses the predictions of all algorithms, finding that a consensus among the different predictive methods consistently exceeds the performance of the best individual pipelines. We screened in human cells the top-ranked drugs, obtaining a 62% success rate, in contrast to the 0.8% hit rate of nonguided screenings. Of the six drugs that reduced viral infection, four could be directly repurposed to treat COVID-19, proposing novel treatments for COVID-19. We also found that 76 of the 77 drugs that successfully reduced viral infection do not bind the proteins targeted by SARS-CoV-2, indicating that these network drugs rely on network-based mechanisms that cannot be identified using docking-based strategies. These advances offer a methodological pathway to identify repurposable drugs for future pathogens and neglected diseases underserved by the costs and extended timeline of de novo drug development.

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Section: Significancementioning

confidence: 99%

Section: Experimental and Clinical Validation Of Drug-repurposing Pipelinesmentioning

confidence: 99%

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Network medicine framework for identifying drug-repurposing opportunities for COVID-19

Gysi

Valle

Žitnik

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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283

200

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“…98 Data from repurposing screens for SARS-CoV-2, in particular for host cell targeted molecules, show more variability based on the assay used and the cell type used, making it difficult to estimate if an antiviral effect can be expected at the previously established clinical exposure (for example, maintaining exposure over the anti-viral EC 90 as noted above). [99][100][101][102][103] This would again support the need for robust clinical investigation, in particular, for generic medicines where the antiviral mechanism is incompletely understood.…”

Section: Discussionmentioning

confidence: 86%

A review of clinical efficacy data supporting emergency use authorization for COVID‐19 therapeutics and lessons for future pandemics

Yoo

Kim

Lü

et al. 2022

Clinical Translational Sci

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Emergency Use Authorization (EUA) allows the US Food and Drug Administration (FDA) to expedite the availability of therapeutics in the context of a public health emergency. To date, an evidentiary standard for clinical efficacy to support an EUA has not yet been established. This review examines the clinical data submitted in support of EUA for antiviral and anti‐inflammatory therapeutics for coronavirus disease 2019 (COVID‐19) through December of 2021 and the resilience of the authorization as new clinical data arose subsequent to the authorization. In the vast majority of cases, EUA was supported by at least one well‐powered randomized controlled trial (RCT) where statistically significant efficacy was demonstrated. This included branded medications already approved for use outside of the context of COVID‐19. When used, the standard of a single RCT seemed to provide adequate evidence of clinical efficacy, such that subsequent clinical studies generally supported or expanded the EUA of the therapeutic in question. The lone generic agent that was granted EUA (chloroquine/hydroxychloroquine) was not supported by a well‐controlled RCT, and the EUA was withdrawn within 3 months time. This highlighted not only the ambiguity of the EUA standard, but also the need to provide avenues through which high quality clinical evidence for the efficacy of a generic medication could be obtained. Therefore, maintaining the clinical trial networks assembled during the COVID‐19 pandemic could be a critical component of our preparation for future pandemics. Consideration could also be given to establishing a single successful RCT as regulatory guidance for obtaining an EUA.

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“…To develop a novel antiviral drug, repurposing of clinically approved drugs for application in the treatment of an emerging viral infection has widely been used in recent years. This strategy is promising for rapidly identifying effective, safe, and readily available clinical candidates for COVID-19 treatment (Dittmar et al, 2021;Gao et al, 2020a;Han et al, 2021;Pandey et al, 2020;Patten et al, 2021;Riva et al, 2020). However, most repurposing investigations have only been performed to screen virus cell culture systems, and there are very few evaluations of efficacy against SARS-CoV-2 in vivo.…”

Section: Introductionmentioning

confidence: 99%

Discovery of potential anti-SARS-CoV-2 drugs based on large-scale screening in vitro and effect evaluation in vivo

Peng

Ding

Jiang

et al. 2021

Sci. China Life Sci.

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The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global crisis. Clinical candidates with high efficacy, ready availability, and that do not develop resistance are in urgent need. Despite that screening to repurpose clinically approved drugs has provided a variety of hits shown to be effective against SARS-CoV-2 infection in cell culture, there are few confirmed antiviral candidates in vivo . In this study, 94 compounds showing high antiviral activity against SARS-CoV-2 in Vero E6 cells were identified from 2,580 FDA-approved small-molecule drugs. Among them, 24 compounds with low cytotoxicity were selected, and of these, 17 compounds also effectively suppressed SARS-CoV-2 infection in HeLa cells transduced with human ACE2. Six compounds disturb multiple processes of the SARS-CoV-2 life cycle. Their prophylactic efficacies were determined in vivo using Syrian hamsters challenged with SARS-CoV-2 infection. Seven compounds reduced weight loss and promoted weight regain of hamsters infected not only with the original strain but also the D614G variant. Except for cisatracurium, six compounds reduced hamster pulmonary viral load, and IL-6 and TNF -α mRNA when assayed at 4 d postinfection. In particular, sertraline, salinomycin, and gilteritinib showed similar protective effects as remdesivir in vivo and did not induce antiviral drug resistance after 10 serial passages of SARS-CoV-2 in vitro , suggesting promising application for COVID-19 treatment. Supporting Information The supporting information is available online at 10.1007/s11427-021-2031-7. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.

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Identification of druggable host targets needed for SARS-CoV-2 infection by combined pharmacological evaluation and cellular network directed prioritization both in vitro and in vivo

Cited by 6 publications

References 66 publications

Network medicine framework for identifying drug-repurposing opportunities for COVID-19

Network medicine framework for identifying drug-repurposing opportunities for COVID-19

A review of clinical efficacy data supporting emergency use authorization for COVID‐19 therapeutics and lessons for future pandemics

Discovery of potential anti-SARS-CoV-2 drugs based on large-scale screening in vitro and effect evaluation in vivo

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