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Dr. Leah Goulding
African Swine Fever Virus, The Pirbright Institute, Pirbright, UK

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0 Antiviral
0 Innate Immunity
0 drug repurposing
0 Influenza A virus
0 African swine fever virus

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Journal article
Published: 03 February 2021 in Viruses
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The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to include antivirals to treat acute infections, in addition to the judicious use of effective vaccines. Whilst COVID-19 vaccines are being rolled out for mass vaccination, the modest number of antivirals in use or development for any disease bears testament to the challenges of antiviral development. We recently showed that non-cytotoxic levels of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase pump, induces a potent host innate immune antiviral response that blocks influenza A virus replication. Here we show that TG is also highly effective in blocking the replication of respiratory syncytial virus (RSV), common cold coronavirus OC43, SARS-CoV-2 and influenza A virus in immortalized or primary human cells. TG’s antiviral performance was significantly better than remdesivir and ribavirin in their respective inhibition of OC43 and RSV. Notably, TG was just as inhibitory to coronaviruses (OC43 and SARS-CoV-2) and influenza viruses (USSR H1N1 and pdm 2009 H1N1) in separate infections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against a lethal influenza virus challenge. Together with its ability to inhibit the different viruses before or during active infection, and with an antiviral duration of at least 48 h post-TG exposure, we propose that TG (or its derivatives) is a promising broad-spectrum inhibitor against SARS-CoV-2, OC43, RSV and influenza virus.

ACS Style

Sarah Al-Beltagi; Cristian Preda; Leah Goulding; Joe James; Juan Pu; Paul Skinner; Zhimin Jiang; Belinda Wang; Jiayun Yang; Ashley Banyard; Kenneth Mellits; Pavel Gershkovich; Christopher Hayes; Jonathan Nguyen-Van-Tam; Ian Brown; Jinhua Liu; Kin-Chow Chang. Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus. Viruses 2021, 13, 234 .

AMA Style

Sarah Al-Beltagi, Cristian Preda, Leah Goulding, Joe James, Juan Pu, Paul Skinner, Zhimin Jiang, Belinda Wang, Jiayun Yang, Ashley Banyard, Kenneth Mellits, Pavel Gershkovich, Christopher Hayes, Jonathan Nguyen-Van-Tam, Ian Brown, Jinhua Liu, Kin-Chow Chang. Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus. Viruses. 2021; 13 (2):234.

Chicago/Turabian Style

Sarah Al-Beltagi; Cristian Preda; Leah Goulding; Joe James; Juan Pu; Paul Skinner; Zhimin Jiang; Belinda Wang; Jiayun Yang; Ashley Banyard; Kenneth Mellits; Pavel Gershkovich; Christopher Hayes; Jonathan Nguyen-Van-Tam; Ian Brown; Jinhua Liu; Kin-Chow Chang. 2021. "Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus." Viruses 13, no. 2: 234.

Journal article
Published: 27 September 2020 in Viruses
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Influenza A virus is a major global pathogen of humans, and there is an unmet need for effective antivirals. Current antivirals against influenza A virus directly target the virus and are vulnerable to mutational resistance. Harnessing an effective host antiviral response is an attractive alternative. We show that brief exposure to low, non-toxic doses of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase pump, promptly elicits an extended antiviral state that dramatically blocks influenza A virus production. Crucially, oral administration of TG protected mice against lethal virus infection and reduced virus titres in the lungs of treated mice. TG-induced ER stress unfolded protein response appears as a key driver responsible for activating a spectrum of host antiviral defences that include an enhanced type I/III interferon response. Our findings suggest that TG is potentially a viable host-centric antiviral for the treatment of influenza A virus infection without the inherent problem of drug resistance.

ACS Style

Leah V. Goulding; Jiayun Yang; Zhimin Jiang; Hongyu Zhang; Daniel Lea; Richard D. Emes; Tania Dottorini; Juan Pu; Jinhua Liu; Kin-Chow Chang. Thapsigargin at Non-Cytotoxic Levels Induces a Potent Host Antiviral Response that Blocks Influenza A Virus Replication. Viruses 2020, 12, 1093 .

AMA Style

Leah V. Goulding, Jiayun Yang, Zhimin Jiang, Hongyu Zhang, Daniel Lea, Richard D. Emes, Tania Dottorini, Juan Pu, Jinhua Liu, Kin-Chow Chang. Thapsigargin at Non-Cytotoxic Levels Induces a Potent Host Antiviral Response that Blocks Influenza A Virus Replication. Viruses. 2020; 12 (10):1093.

Chicago/Turabian Style

Leah V. Goulding; Jiayun Yang; Zhimin Jiang; Hongyu Zhang; Daniel Lea; Richard D. Emes; Tania Dottorini; Juan Pu; Jinhua Liu; Kin-Chow Chang. 2020. "Thapsigargin at Non-Cytotoxic Levels Induces a Potent Host Antiviral Response that Blocks Influenza A Virus Replication." Viruses 12, no. 10: 1093.

Evaluation study
Published: 17 September 2015 in BMC Cell Biology
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Issued under a CC-BY 4.0 licence (http://creativecommons.org/licenses/by/4.0/).BACKGROUND. The traditional problems of performing skeletal muscle cell cultures derived from mammalian or avian species are limited myotube differentiation, and transient myotube persistence which greatly restricts the ability of myotubes to undergo phenotypic maturation. We report here on a major technical breakthrough in the establishment of a simple and effective method of extended porcine myotube cultures (beyond 50 days) in two-dimension (2D) that recapitulates key features of postnatal fibre types. RESULTS. Primary porcine muscle satellite cells (myoblasts) were isolated from the longissimus dorsi of 4 to 6 weeks old\ud pigs for 2D cultures to optimise myotube formation, improve surface adherence and characterise myotube maturation. Over 95% of isolated cells were myoblasts as evidenced by the expression of Pax3 and Pax7. Our relatively simple approach, based on modifications of existing surface coating reagents (Maxgel), and of proliferation and differentiation (Ultroser G) media, typically achieved by 5 days of differentiation fusion index of around 80 % manifested in an abundance of discrete myosin heavy chain (MyHC) slow and fast myotubes. There was little deterioration in myotube viability over 50 days, and the efficiency of myotube formation was maintained over seven myoblast passages. Regular spontaneous contractions of myotubes were frequently observed throughout culture. Myotubes in extended cultures were able to undergo phenotypic adaptation in response to different culture media, including the adoption of a dominant postnatal phenotype of fast-glycolytic MyHC 2x and 2b expression by about day 20 of differentiation. Furthermore, fast-glycolytic myotubes coincided with enhanced expression of the putative porcine long intergenic non-coding RNA (linc-MYH), which has recently been shown to be a key coordinator of MyHC 2b expression in vivo. CONCLUSIONS. Our revised culture protocol allows the efficient differentiation and fusion of porcine myoblasts into myotubes and their prolonged adherence to the culture surface. Furthermore, we are able to recapitulate in 2D the maturation process of myotubes to resemble postnatal fibre types which represent a major technical advance in opening access to the in vitro study of coordinated postnatal muscle gene expression

ACS Style

Sujith Sebastian; Leah Goulding; Suresh V. Kuchipudi; Kin-Chow Chang. Extended 2D myotube culture recapitulates postnatal fibre type plasticity. BMC Cell Biology 2015, 16, 23 .

AMA Style

Sujith Sebastian, Leah Goulding, Suresh V. Kuchipudi, Kin-Chow Chang. Extended 2D myotube culture recapitulates postnatal fibre type plasticity. BMC Cell Biology. 2015; 16 (1):23.

Chicago/Turabian Style

Sujith Sebastian; Leah Goulding; Suresh V. Kuchipudi; Kin-Chow Chang. 2015. "Extended 2D myotube culture recapitulates postnatal fibre type plasticity." BMC Cell Biology 16, no. 1: 23.