Biophysical modeling of the SARS-CoV-2 viral cycle reveals ideal antiviral targets

Castle, Brian T.; Dock, Carissa; Hemmat, Mahya; Kline, Susan; Tignanelli, Christopher J.; Rajasingham, Radha; Masopust, David; Provenzano, Paolo P.; Langlois, Ryan A.; Schacker, Timothy W.; Haase, Ashley T.; Odde, David J.

doi:10.1101/2020.05.22.111237

Cited by 12 publications

(14 citation statements)

References 33 publications

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“…This model predicted that targeting of transcription and translation are especially sensitive processes that could allow effective antiviral targeting of SARS-CoV-2. Consistent with the model predictions the transcription inhibitor N-hydroxycytidine and the translation inhibitors metformin (41,42) and sirolimus were effective in inhibiting viral replication for at least some of the patients. Also consistent with the model predictions, the viral entry inhibitor, chloroquine, was not effective.…”

Section: Discussionsupporting

confidence: 70%

“…Also consistent with the model predictions, the viral entry inhibitor, chloroquine, was not effective. The model failed to predict the lack of effectiveness of remdesivir, which may be due to the specific properties of the drug binding in the cells (41). The model did not make any specific prediction about dexamethasone, which targets immunomodulators.…”

Section: Discussionmentioning

confidence: 87%

“…Our in vitro lung tissue assay allowed us to test the predictions of a biophysical model for the SARS-CoV-2 life cycle (41). This model predicted that targeting of transcription and translation are especially sensitive processes that could allow effective antiviral targeting of SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

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In vitroinfection of human lung tissue with SARS-CoV-2: Heterogeneity in host defense and therapeutic response

Schaller

Sharma

Dupee

et al. 2021

Preprint

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Cell lines are the mainstay in understanding the biology of COVID-19 infection, but do not recapitulate many of the complexities of human infection. The use of human lung tissue is one solution for the study of such novel respiratory pathogens. We hypothesized that a cryopreserved bank of human lung tissue allows for the in vitro study of the inter-individual heterogeneity of host response to SARS-CoV-2 infection, thus providing a bridge between studies with cell lines and studies in animal models. We generated a cryobank of tissues from 16 donors, most of whom had risk factors for severe illness from COVID-19. Cryopreserved tissues preserved 90% of cell viability and contained heterogeneous populations of metabolically active epithelial, endothelial, and immune cell subsets of the human lung. Samples were readily infectible with HCoV-OC43 and SARS-CoV-2 coronavirus strains, and demonstrated comparable susceptibility to infection. In contrast, we observed a marked donor-dependent heterogeneity in the expression of IL-6, CXCL8 and IFNβ in response to SARS-CoV-2 infection. Treatment of tissues with dexamethasone and the experimental drug, N-hydroxycytidine, suppressed viral growth in all samples, whereas chloroquine and remdesivir had no detectable effect. Metformin and sirolimus, molecules with predicted antiviral activity, suppressed viral replication in tissues from a subset of donors. In summary, we developed a novel system for the in vitro study of human SARS-CoV-2 infection using primary human lung tissue from a library of donor tissues. This model may be useful for drug screening and for understanding basic mechanisms of COVID-19 pathogenesis.ImportanceThe current biological systems for the study of COVID-19 are in vitro systems that differ from the human lung in many respects, and animal hosts to which the virus is not adapted. We developed another alternative for studying pathogenesis and drug susceptibility of SARS-CoV-2 in a cryopreserved bank of human lung tissues. We consider the importance of this work to relate to the practical use of this culture system as a repeatable and scalable approach that allows for the study of an important infection in relevant tissues.The tissue bank highlights the heterogeneous response to SARS-CoV-2 infection and treatment, which allows researchers to investigate why treatments work in some donors but not others.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 87%

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In vitroinfection of human lung tissue with SARS-CoV-2: Heterogeneity in host defense and therapeutic response

Schaller

Sharma

Dupee

et al. 2021

Preprint

Self Cite

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“…However, if the SARS‐CoV‐2 cycle and its modulation of cellular pathways is similar to MERS‐CoV and other RNA viruses, this presents a potential target to explore for novel or repurposed treatments. Biophysical modeling of SARS‐Cov2, predicts that targeting of viral transcription, translation, or both, represent high sensitivity targets for therapeutic inhibition and are likely to result in inhibition of viral replication 5 . A SARS‐CoV‐2 human protein‐protein interaction map was recently performed to reveal potential drug targets.…”

Section: Manuscriptmentioning

confidence: 99%

mTOR inhibition in COVID‐19: A commentary and review of efficacy in RNA viruses

Karam

Morris

Bramante

et al. 2020

Journal of Medical Virology

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In this commentary, we shed light on the role of the mammalian target of rapamycin (mTOR) pathway in viral infections. The mTOR pathway has been demonstrated to be modulated in numerous RNA viruses. Frequently, inhibiting mTOR results in suppression of virus growth and replication. Recent evidence points towards modulation of mTOR in severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. We discuss the current literature on mTOR in SARS‐CoV‐2 and highlight evidence in support of a role for mTOR inhibitors in the treatment of coronavirus disease 2019.

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“…In Ref. [ 36 • ], exhaustive combinatorial sensitivity analysis for all pairwise parameter changes in a model of the SARS-CoV-2 viral life cycle predicted that drugs targeting viral genome replication (like remdesivir ) and protein synthesis would result in the most effective reduction of viral titer.…”

Section: How Understanding Viral Kinetics and Immune Response Can Assist Development Of Antiviral Therapiesmentioning

confidence: 99%

Advancing therapies for viral infections using mechanistic computational models of the dynamic interplay between the virus and host immune response

Zarnitsyna

Gianlupi

Hagar

et al. 2021

Current Opinion in Virology

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The COVID-19 pandemic has highlighted a need for improved frameworks for drug discovery, repurposing, clinical trial design and therapy optimization and personalization. Mechanistic computational models can play an important role in developing these frameworks. We discuss how mechanistic models, which consider viral entry, replication in target cells, viral spread in the body, immune response, and the complex factors involved in tissue and organ damage and recovery, can clarify the mechanisms of humoral and cellular immune responses to the virus, viral distribution and replication in tissues, the origins of pathogenesis and patient-to-patient heterogeneity in responses. These models are already improving our understanding of the mechanisms of action of antivirals and immune modulators. We discuss how closer collaboration between the experimentalists, clinicians and modelers could result in more predictive models which may guide therapies for viral infections, improving survival and leading to faster and more complete recovery.

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Biophysical modeling of the SARS-CoV-2 viral cycle reveals ideal antiviral targets

Cited by 12 publications

References 33 publications

In vitroinfection of human lung tissue with SARS-CoV-2: Heterogeneity in host defense and therapeutic response

In vitroinfection of human lung tissue with SARS-CoV-2: Heterogeneity in host defense and therapeutic response

mTOR inhibition in COVID‐19: A commentary and review of efficacy in RNA viruses

Advancing therapies for viral infections using mechanistic computational models of the dynamic interplay between the virus and host immune response

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