2016 Sep 12;90(19):8924-33. doi: 10.1128/JVI.01429-16. Print 2016 Oct 1. Abelson
Kinase Inhibitors Are Potent Inhibitors of Severe Acute Respiratory
Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus
Fusion. Coleman CM1, Sisk JM1, Mingo RM2, Nelson EA2, White JM2, Frieman MB3.
Abstract
Abstract
The
highly pathogenic severe acute respiratory syndrome coronavirus
(SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV)
cause significant morbidity and mortality. There is currently no approved
therapeutic for highly pathogenic coronaviruses, even as MERS-CoV is
spreading throughout the Middle East.
We previously screened a library of FDA-approved drugs for inhibitors of coronavirus replication in which we identified Abelson (Abl) kinase inhibitors, including the anticancer drug imatinib, as inhibitors of both SARS-CoV and MERS-CoV in vitro
Here we show that the anti-CoV activity of imatinib occurs at the early stages of infection, after internalization and endosomal trafficking, by inhibiting fusion of the virions at the endosomal membrane. We specifically identified the imatinib target,
Abelson tyrosine-protein kinase 2 (Abl2), as required for efficient SARS-CoV and MERS-CoV replication in vitro
These data demonstrate that specific approved drugs can be characterized in vitro for their anticoronavirus activity and used to identify host proteins required for coronavirus replication. This type of study is an important step in the repurposing of approved drugs for treatment of emerging coronaviruses.
IMPORTANCE:
Both SARS-CoV and MERS-CoV are zoonotic infections, with bats as the primary source. The 2003 SARS-CoV outbreak began in Guangdong Province in China and spread to humans via civet cats and raccoon dogs in the wet markets before spreading to 37 countries. The virus caused 8,096 confirmed cases of SARS and 774 deaths (a case fatality rate of ∼10%). The MERS-CoV outbreak began in Saudi Arabia and has spread to 27 countries. MERS-CoV is believed to have emerged from bats and passed into humans via camels. The ongoing outbreak of MERS-CoV has resulted in 1,791 cases of MERS and 640 deaths (a case fatality rate of 36%).
The emergence of SARS-CoV and MERS-CoV provides evidence that coronaviruses are currently spreading from zoonotic sources and can be highly pathogenic, causing serious morbidity and mortality in humans. Treatment of SARS-CoV and MERS-CoV infection is limited to providing supportive therapy consistent with any serious lung disease, as no specific drugs have been approved as therapeutics. Highly pathogenic coronaviruses are rare and appear to emerge and disappear within just a few years. Currently, MERS-CoV is still spreading, as new infections continue to be reported.
The outbreaks of SARS-CoV and MERS-CoV and the continuing diagnosis of new MERS cases highlight the need for finding therapeutics for these diseases and potential future coronavirus outbreaks. Screening FDA-approved drugs streamlines the pipeline for this process, as these drugs have already been tested for safety in humans.
We previously screened a library of FDA-approved drugs for inhibitors of coronavirus replication in which we identified Abelson (Abl) kinase inhibitors, including the anticancer drug imatinib, as inhibitors of both SARS-CoV and MERS-CoV in vitro
Here we show that the anti-CoV activity of imatinib occurs at the early stages of infection, after internalization and endosomal trafficking, by inhibiting fusion of the virions at the endosomal membrane. We specifically identified the imatinib target,
Abelson tyrosine-protein kinase 2 (Abl2), as required for efficient SARS-CoV and MERS-CoV replication in vitro
These data demonstrate that specific approved drugs can be characterized in vitro for their anticoronavirus activity and used to identify host proteins required for coronavirus replication. This type of study is an important step in the repurposing of approved drugs for treatment of emerging coronaviruses.
IMPORTANCE:
Both SARS-CoV and MERS-CoV are zoonotic infections, with bats as the primary source. The 2003 SARS-CoV outbreak began in Guangdong Province in China and spread to humans via civet cats and raccoon dogs in the wet markets before spreading to 37 countries. The virus caused 8,096 confirmed cases of SARS and 774 deaths (a case fatality rate of ∼10%). The MERS-CoV outbreak began in Saudi Arabia and has spread to 27 countries. MERS-CoV is believed to have emerged from bats and passed into humans via camels. The ongoing outbreak of MERS-CoV has resulted in 1,791 cases of MERS and 640 deaths (a case fatality rate of 36%).
The emergence of SARS-CoV and MERS-CoV provides evidence that coronaviruses are currently spreading from zoonotic sources and can be highly pathogenic, causing serious morbidity and mortality in humans. Treatment of SARS-CoV and MERS-CoV infection is limited to providing supportive therapy consistent with any serious lung disease, as no specific drugs have been approved as therapeutics. Highly pathogenic coronaviruses are rare and appear to emerge and disappear within just a few years. Currently, MERS-CoV is still spreading, as new infections continue to be reported.
The outbreaks of SARS-CoV and MERS-CoV and the continuing diagnosis of new MERS cases highlight the need for finding therapeutics for these diseases and potential future coronavirus outbreaks. Screening FDA-approved drugs streamlines the pipeline for this process, as these drugs have already been tested for safety in humans.
Copyright © 2016, American Society for Microbiology. All Rights Reserve
Lisätieto: ABL2 geenistä ( 1q25.2)
- ABL2
- ABL proto-oncogene 2, non-receptor tyrosine kinaseprovided by HGNC
- Also known as
- ARG; ABLL
- Summary
- This gene encodes a member of the Abelson family of nonreceptor tyrosine protein kinases. The protein is highly similar to the c-abl oncogene 1 protein, including the tyrosine kinase, SH2 and SH3 domains, and it plays a role in cytoskeletal rearrangements through its C-terminal F-actin- and microtubule-binding sequences. This gene is expressed in both normal and tumor cells, and is involved in translocation with the ets variant 6 gene in leukemia. Multiple alternatively spliced transcript variants encoding different protein isoforms have been found for this gene. [provided by RefSeq, Nov 2009]
- ExpressionUbiquitous expression in gall bladder (RPKM 5.8), appendix (RPKM 2.3) and 25 other tissues See more
- Preferred Names
- tyrosine-protein kinase ABL2
- Names
- Abelson tyrosine-protein kinase 2
- abelson-related gene protein
- c-abl oncogene 2, non-receptor tyrosine kinase
- tyrosine-protein kinase ARG
- v-abl Abelson murine leukemia viral oncogene homolog 2
- Lisätietoja:
Exp Cell Res. 2013 Aug 1;319(13):2091-102. doi: 10.1016/j.yexcr.2013.05.012. Epub 2013 May 23.One
isoform of Arg/Abl2 tyrosine kinase is nuclear and the other seven
cytosolic isoforms differently modulate cell morphology, motility and
the cytoskeleton.
Bianchi C1, Torsello B et al.Abstract
The non-receptor tyrosine kinase
Abelson related gene (Arg/Abl2) regulates cell migration and
morphogenesis by modulating the cytoskeleton. Arg promotes actin-based
cell protrusions and spreading, and inhibits cell migration by
attenuating stress fiber formation and contractility via activation of
the RhoA inhibitor, p190RhoGAP, and by regulating focal adhesion
dynamics also via CrkII phosphorylation. Eight full-length Arg isoforms
with different N- and C-termini are endogenously expressed in human
cells. In this paper, the eight Arg isoforms, subcloned in the
pFLAG-CMV2 vector, were transfected in COS-7 cells in order to study
their subcellular distribution and role in cell morphology, migration
and cytoskeletal modulation. The transfected 1BSCTS Arg isoform has a
nuclear distribution and phosphorylates CrkII in the nucleus, whilst the
other isoforms are detected in the cytoplasm. The 1BLCTL, 1BSCTL,
1ASCTS isoforms were able to significantly decrease stress fibers,
induce cell shrinkage and filopodia-like protrusions with a significant
increase in p190RhoGAP phosphorylation. In contrast, 1ALCTL, 1ALCTS,
1ASCTL and 1BLCTS isoforms do not significantly decrease stress fibers
and induce the formation of retraction tail-like protrusions. The 1BLCTL
and 1ALCTL isoforms have different effects on cell migration and focal
adhesions. All these data may open new perspectives to study the
mechanisms of cell invasiveness.Isoformi d
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