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David Cowburn - One of the best experts on this subject based on the ideXlab platform.
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Abl Kinase constructs expressed in bacteria: facilitation of structural and functional studies including segmental labeling by expressed protein ligation
Molecular bioSystems, 2012Co-Authors: Dongsheng Liu, David CowburnAbstract:A great portion of tyrosine Kinases are involved in cell development and their structural alteration is intimately involved in associated pathologies of development and oncology. These Kinases are one of the major groups of targets under investigation for molecular therapeutics. To carry out biochemical and structural biological studies on these Kinases, economical production of their purified forms is highly desirable. However over-expressing tyrosine Kinases as recombinant forms in bacterial systems and their purification is a significant challenge. Abelson Kinase (Abl) has previously been expressed on a large scale to facilitate X-ray crystallography and NMR structure studies mainly in baculovirus infected insect cells. Even though success has been achieved in expression of soluble tyrosine Kinases in E. coli with chaperones to improve correct folding, low expression levels of Kinases are intrinsic in such systems because of diversion of resources to produce chaperones. Here we present a straightforward method to express and purify isolated Abl Kinase domain and SH3–SH2–Kinase multi-domain structures. The expressed Abl protein retains its correct folding and biological function. The yield of soluble protein is in a several mg L−1 range in minimal media. Furthermore we demonstrate that segmental isotopic labelling using expressed protein ligation can be achieved using bacterial expressed Abl Kinase domain constructs, which is especially useful in NMR structure–activity studies.
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determination of the rotational diffusion tensor of macromolecules in solution from nmr relaxation data with a combination of exact and approximate methods application to the determination of interdomain orientation in multidomain proteins
Journal of Magnetic Resonance, 2001Co-Authors: Ranajeet Ghose, David Fushman, David CowburnAbstract:In this paper we present a method for determining the rotational diffusion tensor from NMR relaxation data using a combination of approximate and exact methods. The approximate method, which is computationally less intensive, computes values of the principal components of the diffusion tensor and estimates the Euler angles, which relate the principal axis frame of the diffusion tensor to the molecular frame. The approximate values of the principal components are then used as starting points for an exact calculation by a downhill simplex search for the principal components of the tensor over a grid of the space of Euler angles relating the diffusion tensor frame to the molecular frame. The search space of Euler angles is restricted using the tensor orientations calculated using the approximate method. The utility of this approach is demonstrated using both simulated and experimental relaxation data. A quality factor that determines the extent of the agreement between the measured and predicted relaxation data is provided. This approach is then used to estimate the relative orientation of SH3 and SH2 domains in the SH(32) dual-domain construct of Abelson Kinase complexed with a consolidated ligand.
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Solid-Phase Synthesis of Consolidated Ligands Containing an Intramolecular Lactam Bridge: Comparison of Strategies and Tactics
Peptides: The Wave of the Future, 2001Co-Authors: Jaya T. Varkey, David Cowburn, George BaranyAbstract:Src homology (SH) domains are building blocks involved in intracellular signal transduction [1]. Previous work has defined and demonstrated consolidated ligands, which combine in the same molecule peptide sequences recognized by SH2 and SH3 domains (i.e., Pro-Val-pTyr-Glu-Asn-Val and Pro-Pro-Ala-Tyr-Pro-Pro-Pro-Pro-Val-Pro, respectively), and exhibit enhanced affinities and specificities towards dual SH(32) Abelson Kinase [2,3]. For first-generation consolidated ligands, binding sequences were connected by a flexible linker, e.g., Glyn. With the goal to further improve their efficacies, several second-generation consolidated ligands with a more rigid linker, e.g., Alan, and optionally including an intramolecular lactam bridge “lock”, were designed and synthesized [4]. The present report focuses on the 32-residue structure shown below, which contains an i to i+7 lactam bridge to connect the side-chains of Glu and Lys, with an intervening 5-aminovaleric acid (Ava) as a spacer. Two different solid-phase synthetic strategies were evaluated.
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DIRECT DETERMINATION OF CHANGES OF INTERDOMAIN ORIENTATION ON LIGATION : USE OF THE ORIENTATIONAL DEPENDENCE OF 15N NMR RELAXATION IN ABL SH(32)
Biochemistry, 1999Co-Authors: David Fushman, David CowburnAbstract:The relative orientation and motions of domains within many proteins are key to the control of multivalent recognition, or the assembly of protein-based cellular machines. Current methods of structure determination have limited applicability to macromolecular assemblies, characterized by weak interactions between the constituents. Crystal structures of such complexes might be biased by packing forces comparable to the interdomain interactions, while the precision and accuracy of the conventional NMR structural approaches are necessarily limited by the restricted number of NOE contacts and by interdomain flexibility rendering the available NOE information uninterpretable. NMR relaxation studies are capable of providing “long-range” structural information on macromolecules in their native milieu. Here we determine directly the change in domain orientation between unligated and dual ligated subdomains of the SH(32) segment of Abelson Kinase in solution, using the orientational dependence of nuclear spin rela...
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Synthesis and characterization of branched phosphopeptides: Prototype consolidated ligands for SH(32) domains
Letters in Peptide Science, 1996Co-Authors: Jie Zheng, David Cowburn, George BaranyAbstract:This paper details the solid-phase synthesis by N ^α-9-fluorenylmethyloxycarbonyl (Fmoc) chemistry of a series of bivalent consolidated ligands, branched peptides with lengths of 22 to 25 residues. The target peptides were designed to, and in fact do, interact with greater specificity and higher affinity with the SH2 and SH3 domains of Abelson Kinase in an SH(32) dual domain construct. Fmoc- O -phospho- l -tyrosine[Fmoc-Tyr(PO_3H_2)-OH] was used to introduce the required phosphotyrosine residues, and Fmoc- N ^ε-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl- l -lysine [Fmoc-Lys(Dde)-OH] was used to introduce a branch point that allowed proper orientation of individual ligands. The resultant product peptides were characterized by amino acid analyses and electrospray mass spectra.
Mark Peifer - One of the best experts on this subject based on the ideXlab platform.
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The Crk adapter protein is essential for Drosophila embryogenesis, where it regulates multiple actin-dependent morphogenic events.
Molecular biology of the cell, 2019Co-Authors: Andrew J. Spracklen, Emma M. Thornton-kolbe, Alison N. Bonner, Alexandru Florea, Peter J. Compton, Rodrigo Fernandez-gonzalez, Mark PeiferAbstract:Small Src homology domain 2 (SH2) and 3 (SH3) adapter proteins regulate cell fate and behavior by mediating interactions between cell surface receptors and downstream signaling effectors in many signal transduction pathways. The CT10 regulator of Kinase (Crk) family has tissue-specific roles in phagocytosis, cell migration, and neuronal development and mediates oncogenic signaling in pathways like that of Abelson Kinase. However, redundancy among the two mammalian family members and the position of the Drosophila gene on the fourth chromosome precluded assessment of Crk’s full role in embryogenesis. We circumvented these limitations with short hairpin RNA and CRISPR technology to assess Crk’s function in Drosophila morphogenesis. We found that Crk is essential beginning in the first few hours of development, where it ensures accurate mitosis by regulating orchestrated dynamics of the actin cytoskeleton to keep mitotic spindles in syncytial embryos from colliding. In this role, it positively regulates cortical localization of the actin-related protein 2/3 complex (Arp2/3), its regulator suppressor of cAMP receptor (SCAR), and filamentous actin to actin caps and pseudocleavage furrows. Crk loss leads to the loss of nuclei and formation of multinucleate cells. We also found roles for Crk in embryonic wound healing and in axon patterning in the nervous system, where it localizes to the axons and midline glia. Thus, Crk regulates diverse events in embryogenesis that require orchestrated cytoskeletal dynamics.
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The Crk adapter protein is essential for Drosophila embryogenesis, where it regulates multiple actin-dependent morphogenic events
2019Co-Authors: Andrew J. Spracklen, Emma M. Thornton-kolbe, Alison N. Bonner, Alexandru Florea, Peter J. Compton, Rodrigo Fernandez-gonzalez, Mark PeiferAbstract:Abstract Small SH2/SH3 adapter proteins regulate cell fate and behavior by mediating interactions between cell surface receptors and downstream signaling effectors in many signal transduction pathways. The Crk family has tissue-specific roles in phagocytosis, cell migration and neuronal development, and mediates oncogenic signaling in pathways like that of Abelson Kinase. However, redundancy among the two mammalian family members and the position of the Drosophila gene on the fourth chromosome precluded assessment of Crk’s full role in embryogenesis. We circumvented these limitations with shRNA and CRISPR technology to assess Crk’s function in Drosophila morphogenesis. We found Crk is essential beginning in the first few hours of development, where it ensures accurate mitosis by regulating orchestrated dynamics of the actin cytoskeleton to keep mitotic spindles in syncytial embryos from colliding. In this role, it positively regulates levels of the Arp2/3 complex, its regulator SCAR, and F-actin in actin caps and pseudocleavage furrows. Crk loss leads to loss of nuclei and formation of multinucleate cells. We also found roles for Crk in embryonic wound healing and in axon patterning in the nervous system, where it localizes to the axons and midline glia. Thus, Crk regulates diverse events in embryogenesis that require orchestrated cytoskeletal dynamics.
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Abelson Kinase Acts as a Robust, Multifunctional Scaffold in Regulating Embryonic Morphogenesis
Molecular biology of the cell, 2016Co-Authors: Edward M. Rogers, Andrew J. Spracklen, Colleen G. Bilancia, Kaelyn D. Sumigray, S. Colby Allred, Stephanie H. Nowotarski, Kristina N. Schaefer, Benjamin J. Ritchie, Mark PeiferAbstract:Abelson family Kinases (Abls) are key regulators of cell behavior and the cytoskeleton during development and in leukemia. Abl's SH3, SH2, and tyrosine Kinase domains are joined via a linker to an F-actin-binding domain (FABD). Research on Abl's roles in cell culture led to several hypotheses for its mechanism of action: 1) Abl phosphorylates other proteins, modulating their activity, 2) Abl directly regulates the cytoskeleton via its cytoskeletal interaction domains, and/or 3) Abl is a scaffold for a signaling complex. The importance of these roles during normal development remains untested. We tested these mechanistic hypotheses during Drosophila morphogenesis using a series of mutants to examine Abl's many cell biological roles. Strikingly, Abl lacking the FABD fully rescued morphogenesis, cell shape change, actin regulation, and viability, whereas Kinase-dead Abl, although reduced in function, retained substantial rescuing ability in some but not all Abl functions. We also tested the function of four conserved motifs in the linker region, revealing a key role for a conserved PXXP motif known to bind Crk and Abi. We propose that Abl acts as a robust multidomain scaffold with different protein motifs and activities contributing differentially to diverse cellular behaviors.
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Enabled and Capping protein play important roles in shaping cell behavior during Drosophila oogenesis
Developmental biology, 2009Co-Authors: Julie Gates, Stephanie H. Nowotarski, Hongyan Yin, James P. Mahaffey, Tina Bridges, Cristina Herrera, Catarina C. F. Homem, Florence Janody, Denise J. Montell, Mark PeiferAbstract:During development, cells craft an impressive array of actin-based structures, mediating events as diverse as cytokinesis, apical constriction, and cell migration. One challenge is to determine how cells regulate actin assembly and disassembly to carry out these cell behaviors. During Drosophila oogenesis diverse cell behaviors are seen in the soma and germline. We used oogenesis to explore developmental roles of two important actin regulators: Enabled/VASP proteins and Capping protein. We found that Enabled plays an important role in cortical integrity of nurse cells, formation of robust bundled actin filaments in late nurse cells that facilitate nurse cell dumping, and migration of somatic border cells. During nurse cell dumping, Enabled localizes to barbed ends of the nurse cell actin filaments, suggesting its mechanism of action. We further pursued this mechanism using mutant Enabled proteins, each affecting one of its protein domains. These data suggest critical roles for the EVH2 domain and its tetramerization subdomain, while the EVH1 domain appears less critical. Enabled appears to be negatively regulated during oogenesis by Abelson Kinase. We also explored the function of Capping protein. This revealed important roles in oocyte determination, nurse cell cortical integrity and nurse cell dumping, and support the idea that Capping protein and Enabled act antagonistically during dumping. Together these data reveal places that these actin regulators shape oogenesis.
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Abelson Kinase (Abl) and RhoGEF2 regulate actin organization during cell constriction in Drosophila.
Development (Cambridge England), 2007Co-Authors: Donald T. Fox, Mark PeiferAbstract:Morphogenesis involves the interplay of different cytoskeletal regulators. Investigating how they interact during a given morphogenetic event will help us understand animal development. Studies of ventral furrow formation, a morphogenetic event during Drosophila gastrulation, have identified a signaling pathway involving the G-protein Concertina (Cta) and the Rho activator RhoGEF2. Although these regulators act to promote stable myosin accumulation and apical cell constriction, loss-of-function phenotypes for each of these pathway members is not equivalent, suggesting the existence of additional ventral furrow regulators. Here, we report the identification of Abelson Kinase (Abl) as a novel ventral furrow regulator. We find that Abl acts apically to suppress the accumulation of both Enabled (Ena) and actin in mesodermal cells during ventral furrow formation. Further, RhoGEF2 also regulates ordered actin localization during ventral furrow formation, whereas its activator, Cta, does not. Taken together, our data suggest that there are two crucial preconditions for apical constriction in the ventral furrow: myosin stabilization/activation, regulated by Cta and RhoGEF2; and the organization of apical actin, regulated by Abl and RhoGEF2. These observations identify an important morphogenetic role for Abl and suggest a conserved mechanism for this Kinase during apical cell constriction.
Naoki Watanabe - One of the best experts on this subject based on the ideXlab platform.
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Abi-1-bridged tyrosine phosphorylation of VASP by Abelson Kinase impairs association of VASP to focal adhesions and regulates leukaemic cell adhesion.
The Biochemical journal, 2012Co-Authors: Masahiro Maruoka, Yunfeng Yuan, Mizuho Sato, Takuya Ogawa, Norihiro Ishida-kitagawa, Tatsuo Takeya, Masayoshi Ichiba, Ryosuke Fujii, Naoki WatanabeAbstract:Mena [mammalian Ena (Enabled)]/VASP (vasodilator-stimulated phosphoprotein) proteins are the homologues of Drosophila Ena. In Drosophila, Ena is a substrate of the tyrosine Kinase DAbl (Drosophila Abl). However, the link between Abl and the Mena/VASP family is not fully understood in mammals. We previously reported that Abi-1 (Abl interactor 1) promotes phosphorylation of Mena and BCAP (B-cell adaptor for phosphoinositide 3-Kinase) by bridging the interaction between c-Abl and the substrate. In the present study we have identified VASP, another member of the Mena/VASP family, as an Abi-1-bridged substrate of Abl. VASP is phosphorylated by Abl when Abi-1 is co-expressed. We also found that VASP interacted with Abi-1 both in vitro and in vivo. VASP was tyrosine-phosphorylated in Bcr-Abl-positive leukaemic cells in an Abi-1-dependent manner. Co-expression of c-Abl and Abi-1 or the phosphomimetic Y39D mutation in VASP resulted in less accumulation of VASP at focal adhesions. VASP Y39D had a reduced affinity to the proline-rich region of zyxin. Interestingly, overexpression of both phosphomimetic and unphosphorylated forms of VASP, but not wild-type VASP, impaired adhesion of K562 cells to fibronectin. These results suggest that the phosphorylation and dephosphorylation cycle of VASP by the Abi-1-bridged mechanism regulates association of VASP with focal adhesions, which may regulate adhesion of Bcr-Abl-transformed leukaemic cells.
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Imatinib mesylate (STI571)-induced cell edge translocation of Kinase-active and Kinase-defective Abelson Kinase: requirements of myristoylation and src homology 3 domain.
Molecular pharmacology, 2008Co-Authors: Akiko Fujita, Tomoyuki Shishido, Yunfeng Yuan, Eiji Inamoto, Shuh Narumiya, Naoki WatanabeAbstract:4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate (STI571) is the first successful target-based drug with excellent potency against chronic myelogenous leukemia. Studies on this compound have illuminated potentials and problems of Kinase inhibitors in the treatment of cancer. As found in crystal structures, STI571-bound Abelson Kinase (abl) is believed to form closed conformation with N-terminal regulatory domains. Here we present evidence of distinct STI571-induced modulation of abl functions using high-resolution live-cell imaging approaches. Within lamellipodia of fibroblast cells, STI571 was found to induce rapid translocation of abl to the lamellipodium tip. Quantitative analysis yielded 0.81 and 1.8 μM for EC50 values of STI571-induced cell edge translocation of abl-KD-green fluorescent protein (GFP) and wild-type abl-GFP, respectively. It also revealed adverse response of drug-resistant abl-T334I to STI571, suggesting that drug binding to abl-GFP triggers translocation. N-myristoylation and the src homology 3 (SH3) domain were required for this translocation, whereas disruption of intramolecular interactions of these motifs enhanced cell-edge association of abl. An intact C-terminal last exon region in abl, but not its F-actin binding, was required for efficient cell-edge translocation. Moreover, single-molecule observation revealed an STI571-induced rapid increase in slow diffusive species of abl in both the tip and the body region of lamellipodia. These results suggest that although activated abl translocates to the cell edge at its open state, STI571 can also bind and lock abl in the open and membrane-tethered conformation as long as the SH3 domain and the C-terminal region are intact. High-resolution imaging can be a powerful tool for elucidating inhibitor modulation of abl functions under intracellular environment.
George Barany - One of the best experts on this subject based on the ideXlab platform.
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Solid-Phase Synthesis of Consolidated Ligands Containing an Intramolecular Lactam Bridge: Comparison of Strategies and Tactics
Peptides: The Wave of the Future, 2001Co-Authors: Jaya T. Varkey, David Cowburn, George BaranyAbstract:Src homology (SH) domains are building blocks involved in intracellular signal transduction [1]. Previous work has defined and demonstrated consolidated ligands, which combine in the same molecule peptide sequences recognized by SH2 and SH3 domains (i.e., Pro-Val-pTyr-Glu-Asn-Val and Pro-Pro-Ala-Tyr-Pro-Pro-Pro-Pro-Val-Pro, respectively), and exhibit enhanced affinities and specificities towards dual SH(32) Abelson Kinase [2,3]. For first-generation consolidated ligands, binding sequences were connected by a flexible linker, e.g., Glyn. With the goal to further improve their efficacies, several second-generation consolidated ligands with a more rigid linker, e.g., Alan, and optionally including an intramolecular lactam bridge “lock”, were designed and synthesized [4]. The present report focuses on the 32-residue structure shown below, which contains an i to i+7 lactam bridge to connect the side-chains of Glu and Lys, with an intervening 5-aminovaleric acid (Ava) as a spacer. Two different solid-phase synthetic strategies were evaluated.
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Synthesis and characterization of branched phosphopeptides: Prototype consolidated ligands for SH(32) domains
Letters in Peptide Science, 1996Co-Authors: Jie Zheng, David Cowburn, George BaranyAbstract:This paper details the solid-phase synthesis by N ^α-9-fluorenylmethyloxycarbonyl (Fmoc) chemistry of a series of bivalent consolidated ligands, branched peptides with lengths of 22 to 25 residues. The target peptides were designed to, and in fact do, interact with greater specificity and higher affinity with the SH2 and SH3 domains of Abelson Kinase in an SH(32) dual domain construct. Fmoc- O -phospho- l -tyrosine[Fmoc-Tyr(PO_3H_2)-OH] was used to introduce the required phosphotyrosine residues, and Fmoc- N ^ε-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl- l -lysine [Fmoc-Lys(Dde)-OH] was used to introduce a branch point that allowed proper orientation of individual ligands. The resultant product peptides were characterized by amino acid analyses and electrospray mass spectra.
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Synthesis and characterization of branched phosphopeptides: Prototype consolidated ligands for SH(32) domains
Letters in Peptide Science, 1996Co-Authors: Jie Zheng, David Cowburn, George BaranyAbstract:This paper details the solid-phase synthesis by Nα-9-fluorenylmethyloxycarbonyl (Fmoc) chemistry of a series of bivalent consolidated ligands, branched peptides with lengths of 22 to 25 residues. The target peptides were designed to, and in fact do, interact with greater specificity and higher affinity with the SH2 and SH3 domains of Abelson Kinase in an SH(32) dual domain construct. Fmoc-O-phospho-l-tyrosine[Fmoc-Tyr(PO3H2)-OH] was used to introduce the required phosphotyrosine residues, and Fmoc-Ne-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl-l-lysine [Fmoc-Lys(Dde)-OH] was used to introduce a branch point that allowed proper orientation of individual ligands. The resultant product peptides were characterized by amino acid analyses and electrospray mass spectra.
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Enhanced Affinities and Specificities of Consolidated Ligands for the Src Homology (SH) 3 and SH2 Domains of Abelson Protein-tyrosine Kinase
The Journal of biological chemistry, 1995Co-Authors: David Cowburn, Jie Zheng, George BaranyAbstract:Abstract The possible interrelationships between multiple domains of proteins involved in intracellular signal transduction are complex and not easily investigated. We have synthesized a series of bivalent consolidated ligands, which interact simultaneously with the SH2 and SH3 domain of Abelson Kinase in a SH(32) dual domain construct, a portion of native Abelson Kinase. Affinities were measured by quenching of intrinsic tryptophan fluorescence. Consolidated ligands have enhanced affinity and specificity compared to monovalent equivalents. Affinity is also dependent on the length of the linker joining the two parts, with an optimum distance similar to that expected from structural models of Abl (SH(32). These results suggest that consolidated ligands may be generally useful reagents for probing structural and functional activities of multidomain proteins.
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Topologies of consolidated ligands for the Src homology (SH)3 and SH2 domains of Abelson protein-tyrosine Kinase
American Peptide Symposia, 1Co-Authors: Jie Zheng, George Barany, David CowburnAbstract:Src homology (SH)2 and SH3 domains are found in a variety of proteins involved in the control of cellular signalling and architecture [1,2]. The two domains are frequently found together in the same protein, for example in the Abelson Kinase (Abl). SH2 domains recognize motifs that include key phosphotyrosine residues [3], while SH3 domains recognize sequences with multiple proline residues [4]. The interactions between these domains are poorly understood. Here, we describe an approach called "consolidated" ligands to probe structural and functional activities of multidomain proteins. These ligands, having multiple binding portions, may be expected to bind with high affinity and specificity when a linker between the two affine segments is of the correct orientation and length.
Matthew B. Frieman - One of the best experts on this subject based on the ideXlab platform.
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Abelson Kinase Inhibitors Are Potent Inhibitors of Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus Fusion.
Journal of virology, 2016Co-Authors: Christopher M. Coleman, Jeanne M. Sisk, Rebecca M. Mingo, Elizabeth A. Nelson, Judith M. White, Matthew B. FriemanAbstract:UNLABELLED The highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) cause significant morbidity and morality. 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.
