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, Xin; 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 J.; Loscalzo, Joseph; Žitnik, Marinka; Gummuluru, Suryaram; Namchuk, Mark; Barabási, Albert‐László; Davey, Robert A.

doi:10.2139/ssrn.4038525

Cited by 3 publications

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“…Treatment guidelines for the use of antibody therapies for COVID‐19 are based on “current knowledge of the in vitro activities of the available products against the circulating SARS‐CoV‐2 variants and subvariants.” 97 In vitro data were are also prominently noted in the decision to authorize bebtelovimab 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) 99–103 . 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: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…A highly ranked drug in this screen, obatoclax (a BCL2 inhibitor), was then used in an in vivo assay in mice expressing human angiotensin-converting enzyme 2 (ACE2) in epithelial cells (K18-hACE2 trangenics), the receptor for the viral spike protein, showing significant suppression of PCR-detectable viral titer in mouse lung. 23 The predictive yield of our network-based algorithmic approach to drug repurposing is a marked improvement over conventional approaches. As a stochastic frame of reference, note that the standard 'brute-force' screening method of 12 000 compounds proposed for drug repurposing for SARS-CoV-2 yielded positive results in 0.8%.…”

Section: Network Medicine and Drug Target Identificationmentioning

confidence: 98%

“…In addition, the results of a typical high‐throughput assay are shown, which indicates the ability of the algorithm to predict strongly antiviral drugs (compared with remdesivir as a positive control). A highly ranked drug in this screen, obatoclax (a BCL2 inhibitor), was then used in an in vivo assay in mice expressing human angiotensin‐converting enzyme 2 (ACE2) in epithelial cells (K18‐hACE2 trangenics), the receptor for the viral spike protein, showing significant suppression of PCR‐detectable viral titer in mouse lung 23 …”

Section: Network Medicine and Drug Target Identificationmentioning

confidence: 99%

Molecular interaction networks and drug development: Novel approach to drug target identification and drug repositioning

Loscalzo

2022

The FASEB Journal

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Conventional drug discovery requires identifying a protein target believed to be important for disease mechanism and screening compounds for those that beneficially alter the target's function. While this approach has been an effective one for decades, recent data suggest that its continued success is limited largely owing to the highly prevalent irreducibility of biologically complex systems that govern disease phenotype to a single primary disease driver. Network medicine, a new discipline that applies network science and systems biology to the analysis of complex biological systems and disease, offers a novel approach to overcoming these limitations of conventional drug discovery. Using the comprehensive protein–protein interaction network (interactome) as the template through which subnetworks that govern specific diseases are identified, potential disease drivers are unveiled and the effect of novel or repurposed drugs, used alone or in combination, is studied. This approach to drug discovery offers new and exciting unbiased possibilities for advancing our knowledge of disease mechanisms and precision therapeutics.

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A Deep Integrated Framework for Predicting SARS-CoV2–Human Protein-Protein Interaction

Ray

Lall

Bandyopadhyay

2022

IEEE Trans. Emerg. Top. Comput. Intell.

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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 3 publications

References 0 publications

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

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

Molecular interaction networks and drug development: Novel approach to drug target identification and drug repositioning

A Deep Integrated Framework for Predicting SARS-CoV2–Human Protein-Protein Interaction

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