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Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors

View ORCID ProfileJeanne M. Sisk, View ORCID ProfileMatthew B. Frieman, Carolyn E. Machamer
doi: https://doi.org/10.1101/246991
Jeanne M. Sisk
1Department of Cell Biology, The Johns Hopkins University School of Medicine Baltimore, MD 21205, USA
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  • For correspondence: jsisk2@jhu.edu
Matthew B. Frieman
2Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201
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Carolyn E. Machamer
1Department of Cell Biology, The Johns Hopkins University School of Medicine Baltimore, MD 21205, USA
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ABSTRACT

Enveloped viruses gain entry into host cells by fusing with cellular membranes, a step required for virus replication. Coronaviruses, including the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and infectious bronchitis virus (IBV), fuse at the plasma membrane or use receptor-mediated endocytosis and fuse with endosomes depending on the cell or tissue type. The virus Spike (S) protein mediates fusion with the host cell membrane. We have shown previously that an Abl kinase inhibitor, imatinib, significantly reduces SARS-CoV and MERS-CoV viral titers and prevents endosomal entry by HIV SARS S and MERS S pseudotyped virions. SARS-CoV and MERS-CoV are classified as BSL-3 viruses, which can make experimentation into the cellular mechanisms involved in infection more challenging. Here, we use IBV, a BSL-2 virus, as a model for studying the role of Abl kinase activity during coronavirus infection. We found that imatinib and two specific Abl kinase inhibitors, GNF2 and GNF5, reduce IBV titers by blocking the first round of virus infection. Additionally, all three drugs prevented IBV S-induced syncytia formation prior to the hemifusion step. Our results indicate that membrane fusion (both virus-cell and cell-cell) is blocked in the presence of Abl kinase inhibitors. Studying the effects of Abl kinase inhibitors on IBV will be useful in identifying host cell pathways required for coronavirus infection. This will provide insight into possible therapeutic targets to treat infections by current as well as newly emerging coronaviruses.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 12, 2018.
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Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors
Jeanne M. Sisk, Matthew B. Frieman, Carolyn E. Machamer
bioRxiv 246991; doi: https://doi.org/10.1101/246991
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Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors
Jeanne M. Sisk, Matthew B. Frieman, Carolyn E. Machamer
bioRxiv 246991; doi: https://doi.org/10.1101/246991

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