Identification and Development of Therapeutics for COVID-19

Rando, Halie M.; Wellhausen, Nils; Ghosh, Soumita; Lee, Alexandra; Dattoli, Anna Ada; Hu, Fengling; Byrd, James Brian; Rafizadeh, Diane N.; Lordan, Ronan; Qi, Yajuan; Sun, Yuchen; Brueffer, Christian; Field, Jeffrey; Guebila, Marouen Ben; Jadavji, Nafisa M.; Skelly, Ashwin N.; Ramsundar, Bharath; Wang, Jinhui; Goel, Rishi R.; Park, YoSon; Boca, Simina M.; Gitter, Anthony; Greene, Casey S.

doi:10.1128/msystems.00233-21

Cited by 24 publications

(22 citation statements)

References 339 publications

(501 reference statements)

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“…Furthermore, although several drugs that may provide effective treatments for COVID-19 are currently under clinical trial and awaiting approval [12,13], it is currently unclear if daily life around the world will ever return to that of pre-COVID-19 times.…”

Section: Introductionmentioning

confidence: 99%

Metalloproteinase-dependent and TMPRSS2-independnt cell surface entry pathway of SARS-CoV-2 requires the furin-cleavage site and the S2 domain of spike protein

Yamamoto

Gohda

Kobayashi

et al. 2021

Preprint

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The ongoing global vaccination program to prevent SARS-CoV-2 infection, the causative agent of COVID-19, has had significant success. However, recently virus variants have emerged that can evade the immunity in a host achieved through vaccination. Consequently, new therapeutic agents that can efficiently prevent infection from these new variants, and hence COVID-19 spread are urgently required. To achieve this, extensive characterization of virus-host cell interactions to identify effective therapeutic targets is warranted. Here, we report a cell surface entry pathway of SARS-CoV-2 that exists in a cell type-dependent manner is TMPRSS2-independent but sensitive to various broad-spectrum metalloproteinase inhibitors such as marimastat and prinomastat. Experiments with selective metalloproteinase inhibitors and gene-specific siRNAs revealed that a disintegrin and metalloproteinase 10 (ADAM10) is partially involved in the metalloproteinase pathway. Consistent with our finding that the pathway is unique to SARS-CoV-2 among highly pathogenic human coronaviruses, both the furin cleavage motif in the S1/S2 boundary and the S2 domain of SARS-CoV-2 spike protein are essential for metalloproteinase-dependent entry. In contrast, the two elements of SARS-CoV-2 independently contributed to TMPRSS2-dependent S2 priming. The metalloproteinase pathway is involved in SARS-CoV-2-induced syncytia formation and cytopathicity, leading us to theorize that it is also involved in the rapid spread of SARS-CoV-2 and the pathogenesis of COVID-19. Thus, targeting the metalloproteinase pathway in addition to the TMPRSS2 and endosome pathways could be an effective strategy by which to cure COVID-19 in the future.

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Section: Introductionmentioning

confidence: 99%

Metalloproteinase-dependent and TMPRSS2-independnt cell surface entry pathway of SARS-CoV-2 requires the furin-cleavage site and the S2 domain of spike protein

Yamamoto

Gohda

Kobayashi

et al. 2021

Preprint

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show abstract

“…Collectively, these five groups of keywords showed that during the COVID-19 pandemic, identification of the main viral target proteins and pathogenic mechanisms are important for conducting pharmacological research. Furthermore, drug repurposing and development should be performed to achieve effective viral eradication [25] . In the early phase of the pandemic, prior pharmacological research provided clues for therapeutic schedule exploration.…”

Section: Discussionmentioning

confidence: 99%

COVID-19 pharmacological research trends: a bibliometric analysis

Shi¹,

Song²,

Guo³

et al. 2023

Intelligent Medicine

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“…Despite the surge in research efforts devoted to COVID-19 ( 9 , 10 ), laboratory study of the virus remains a more specialized and time-consuming effort than sequencing. Clinical and epidemiological data are often superficial, measuring only a few variables, other than data sets specific to particular facilities or narrow populations.…”

Section: Perspectivementioning

confidence: 99%

Mapping Data to Deep Understanding: Making the Most of the Deluge of SARS-CoV-2 Genome Sequences

Sokhansanj

Rosen

2022

mSystems

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Identification and Development of Therapeutics for COVID-19

Abstract: The COVID-19 pandemic is a rapidly evolving crisis. With the worldwide scientific community shifting focus onto the SARS-CoV-2 virus and COVID-19, a large number of possible pharmaceutical approaches for treatment and prevention have been proposed.

Cited by 24 publications

References 339 publications

Metalloproteinase-dependent and TMPRSS2-independnt cell surface entry pathway of SARS-CoV-2 requires the furin-cleavage site and the S2 domain of spike protein

Metalloproteinase-dependent and TMPRSS2-independnt cell surface entry pathway of SARS-CoV-2 requires the furin-cleavage site and the S2 domain of spike protein

COVID-19 pharmacological research trends: a bibliometric analysis

Mapping Data to Deep Understanding: Making the Most of the Deluge of SARS-CoV-2 Genome Sequences

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