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Article ; Online: The Next Wave of Influenza Drugs.

Shaw, Megan L

ACS infectious diseases

2017 Volume 3, Issue 10, Page(s) 691–694

Abstract: Options for influenza therapy are currently limited to one class of drug, the neuraminidase inhibitors. Amidst concerns about drug resistance, much effort has been placed on the discovery of new drugs with distinct targets and mechanisms of action, with ... ...

Abstract	Options for influenza therapy are currently limited to one class of drug, the neuraminidase inhibitors. Amidst concerns about drug resistance, much effort has been placed on the discovery of new drugs with distinct targets and mechanisms of action, with great success. There are now several candidates in late stage development which include small molecules targeting the three subunits of the viral polymerase complex and monoclonal antibodies targeting the hemagglutinin, as well as host-directed therapies. The availability of drugs with diverse mechanisms now opens the door to exploring combination therapies for influenza, and the range of administration routes presents more opportunities for treating hospitalized patients.
MeSH term(s)	Antiviral Agents/classification ; Antiviral Agents/therapeutic use ; Drug Discovery ; Humans ; Influenza, Human/drug therapy
Chemical Substances	Antiviral Agents
Language	English
Publishing date	2017-09-11
Publishing country	United States
Document type	Journal Article
ISSN	2373-8227
ISSN (online)	2373-8227
DOI	10.1021/acsinfecdis.7b00142
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Article: Role of Host Genes in Influenza Virus Replication.

Shaw, Megan L / Stertz, Silke

Current topics in microbiology and immunology

2017 Volume 419, Page(s) 151–189

Abstract: At every step of their replication cycle influenza viruses depend heavily on their host cells. The multifaceted interactions that occur between the virus and its host cell determine the outcome of the infection, including efficiency of progeny virus ... ...

Abstract	At every step of their replication cycle influenza viruses depend heavily on their host cells. The multifaceted interactions that occur between the virus and its host cell determine the outcome of the infection, including efficiency of progeny virus production, tropism, and pathogenicity. In order to understand viral disease and develop therapies for influenza it is therefore pertinent to study the intricate interplay between influenza viruses and their required host factors. Here, we review the current knowledge on host cell factors required by influenza virus at the different stages of the viral replication cycle. We also discuss the roles of host factors in zoonotic transmission of influenza viruses and their potential for developing novel antivirals.
MeSH term(s)	Host-Pathogen Interactions/genetics ; Humans ; Influenza, Human/drug therapy ; Influenza, Human/genetics ; Influenza, Human/virology ; Orthomyxoviridae/growth & development ; Orthomyxoviridae/pathogenicity ; Virulence ; Virus Replication
Language	English
Publishing date	2017-06-21
Publishing country	Germany
Document type	Journal Article ; Review
ISSN	0070-217X
ISSN	0070-217X
DOI	10.1007/82_2017_30
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Article ; Online: Baloxavir marboxil: the new influenza drug on the market.

O'Hanlon, Ryan / Shaw, Megan L

Current opinion in virology

2019 Volume 35, Page(s) 14–18

Abstract: For the first time in nearly 20 years there is a new class of antiviral drug for influenza. The latest approved antiviral is baloxavir marboxil (trade name, Xofluza) which targets the endonuclease function of the viral PA polymerase subunit and prevents ... ...

Abstract	For the first time in nearly 20 years there is a new class of antiviral drug for influenza. The latest approved antiviral is baloxavir marboxil (trade name, Xofluza) which targets the endonuclease function of the viral PA polymerase subunit and prevents the transcription of viral mRNA. The most promising aspect of this new drug is its pharmacology which allows for effective treatment of influenza A or B virus infection with just a single dose. A clinical trial showed greater reductions in viral loads with baloxavir marboxil treatment compared with oseltamivir, although no difference in the time to alleviation of symptoms between these two drugs. With this new class of influenza drug comes exciting prospects for combination therapy with the neuraminidase inhibitors which may help to abate concerns about the development of resistance.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Clinical Trials as Topic ; Drug Resistance, Viral ; Humans ; Influenza A virus/drug effects ; Influenza B virus/drug effects ; Influenza, Human/drug therapy ; Orthomyxoviridae/drug effects ; Orthomyxoviridae Infections/drug therapy ; Oxazines/pharmacology ; Pyridines/pharmacology ; Thiepins/pharmacology ; Triazines/pharmacology ; Viral Load/drug effects
Chemical Substances	Antiviral Agents ; Oxazines ; Pyridines ; Thiepins ; Triazines ; baloxavir (4G86Y4JT3F)
Language	English
Publishing date	2019-03-08
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2611378-8
ISSN	1879-6265 ; 1879-6257
ISSN (online)	1879-6265
ISSN	1879-6257
DOI	10.1016/j.coviro.2019.01.006
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Article ; Online: The host interactome of influenza virus presents new potential targets for antiviral drugs.

Shaw, Megan L

Reviews in medical virology

2011 Volume 21, Issue 6, Page(s) 358–369

Abstract: Increasing antiviral drug resistance is a major concern for treating influenza, especially in a pandemic setting when the availability of a protective vaccine is uncertain. Resistance is often an issue with drugs directed at viral proteins and for small ... ...

Abstract	Increasing antiviral drug resistance is a major concern for treating influenza, especially in a pandemic setting when the availability of a protective vaccine is uncertain. Resistance is often an issue with drugs directed at viral proteins and for small RNA viruses; there are also a limited number of viral proteins that are amenable to inhibition by a small molecule. A new approach that is gaining support is that cellular proteins, which facilitate virus replication, may be used as alternative targets. Whereas drugs directed at viral proteins tend to be virus-specific, drugs directed at host targets have the potential to have broad-spectrum antiviral activity as many viruses may share a dependency on that host function. For influenza virus, we have very limited knowledge of which cellular factors are involved in virus replication, let alone which of these have suitable properties to serve as drug targets. Through the use of high-throughput RNA interference screens, several studies have addressed this gap in our knowledge. The resulting datasets provide new insight into host pathways that are involved in the influenza virus replication cycle and identify specific host factors in these pathways that may serve as potential targets for future antiviral drug development.
MeSH term(s)	Antiviral Agents/pharmacology ; Host-Pathogen Interactions/drug effects ; Humans ; Influenza, Human/drug therapy ; Orthomyxoviridae/pathogenicity
Chemical Substances	Antiviral Agents
Keywords	covid19
Language	English
Publishing date	2011-08-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1086043-5
ISSN	1099-1654 ; 1052-9276
ISSN (online)	1099-1654
ISSN	1052-9276
DOI	10.1002/rmv.703
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Article ; Online: Henipaviruses employ a multifaceted approach to evade the antiviral interferon response.

Shaw, Megan L

Viruses

2009 Volume 1, Issue 3, Page(s) 1190–1203

Abstract: Hendra and Nipah virus, which constitute the genus Henipavirus, are zoonotic paramyxoviruses that have been associated with sporadic outbreaks of severe disease and mortality in humans since their emergence in the late 1990s. Similar to other ... ...

Abstract	Hendra and Nipah virus, which constitute the genus Henipavirus, are zoonotic paramyxoviruses that have been associated with sporadic outbreaks of severe disease and mortality in humans since their emergence in the late 1990s. Similar to other paramyxoviruses, their ability to evade the host interferon (IFN) response is conferred by the P gene. The henipavirus P gene encodes four proteins; the P, V, W and C proteins, which have all been described to inhibit the antiviral response. Further studies have revealed that these proteins have overlapping but unique properties which enable the virus to block multiple signaling pathways in the IFN response. The best characterized of these is the JAK-STAT signaling pathway which is targeted by the P, V and W proteins via an interaction with the transcription factor STAT1. In addition the V and W proteins can both limit virus-induced induction of IFN but they appear to do this via distinct mechanisms that rely on unique sequences in their C-terminal domains. The ability to generate recombinant Nipah viruses now gives us the opportunity to determine the precise role for each of these proteins and address their contribution to pathogenicity. Additionally, the question of whether these multiple anti-IFN strategies are all active in the different mammalian hosts for henipaviruses, particularly the fruit bat reservoir, warrants further exploration.
Language	English
Publishing date	2009-12-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v1031190
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Article ; Online: LSDV-Vectored SARS-CoV-2 S and N Vaccine Protects against Severe Clinical Disease in Hamsters.

de Moor, Warren R J / Williamson, Anna-Lise / Schäfer, Georgia / Douglass, Nicola / Gers, Sophette / Sutherland, Andrew D / Blumenthal, Melissa J / Margolin, Emmanuel / Shaw, Megan L / Preiser, Wolfgang / Chapman, Rosamund

Viruses

2023 Volume 15, Issue 7

Abstract: The SARS-CoV-2 pandemic demonstrated the need for potent and broad-spectrum vaccines. This study reports the development and testing of a lumpy skin disease virus (LSDV)-vectored vaccine against SARS-CoV-2, utilizing stabilized spike and conserved ... ...

Abstract	The SARS-CoV-2 pandemic demonstrated the need for potent and broad-spectrum vaccines. This study reports the development and testing of a lumpy skin disease virus (LSDV)-vectored vaccine against SARS-CoV-2, utilizing stabilized spike and conserved nucleocapsid proteins as antigens to develop robust immunogenicity. Construction of the vaccine (LSDV-SARS2-S,N) was confirmed by polymerase chain reaction (PCR) amplification and sequencing. In vitro characterization confirmed that cells infected with LSDV-SARS2-S,N expressed SARS-CoV-2 spike and nucleocapsid protein. In BALB/c mice, the vaccine elicited high magnitude IFN-γ ELISpot responses (spike: 2808 SFU/10
MeSH term(s)	Animals ; Cricetinae ; Cattle ; Mice ; Humans ; SARS-CoV-2/genetics ; COVID-19 Vaccines ; COVID-19/prevention & control ; Lumpy skin disease virus ; Vaccines ; Antibodies, Neutralizing ; Mice, Inbred BALB C ; Nucleocapsid Proteins ; Antibodies, Viral ; Spike Glycoprotein, Coronavirus/genetics
Chemical Substances	COVID-19 Vaccines ; Vaccines ; Antibodies, Neutralizing ; Nucleocapsid Proteins ; Antibodies, Viral ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2023-06-21
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v15071409
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Article ; Online: Successes and challenges in the antiviral field.

Shaw, Megan L / Klumpp, Klaus

Current opinion in virology

2013 Volume 3, Issue 5, Page(s) 483–486

MeSH term(s)	Antiviral Agents/pharmacology ; Humans ; Virus Diseases/drug therapy ; Virus Diseases/virology ; Viruses/drug effects
Chemical Substances	Antiviral Agents
Language	English
Publishing date	2013-10
Publishing country	Netherlands
Document type	Editorial ; Introductory Journal Article
ZDB-ID	2611378-8
ISSN	1879-6265 ; 1879-6257
ISSN (online)	1879-6265
ISSN	1879-6257
DOI	10.1016/j.coviro.2013.08.015
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Article ; Online: An Influenza Virus Entry Inhibitor Targets Class II PI3 Kinase and Synergizes with Oseltamivir.

O'Hanlon, Ryan / Leyva-Grado, Victor H / Sourisseau, Marion / Evans, Matthew J / Shaw, Megan L

ACS infectious diseases

2019 Volume 5, Issue 10, Page(s) 1779–1793

Abstract: Two classes of antivirals targeting the viral neuraminidase (NA) and endonuclease are currently the only clinically useful drugs for the treatment of influenza. However, resistance to both antivirals has been observed in clinical isolates, and there was ... ...

Abstract	Two classes of antivirals targeting the viral neuraminidase (NA) and endonuclease are currently the only clinically useful drugs for the treatment of influenza. However, resistance to both antivirals has been observed in clinical isolates, and there was widespread resistance to oseltamivir (an NA inhibitor) among H1N1 viruses prior to 2009. This potential for resistance and lack of diversity for antiviral targets highlights the need for new influenza antivirals with a higher barrier to resistance. In this study, we identified an antiviral compound, M85, that targets host kinases, epidermal growth factor receptor (EGFR), and phosphoinositide 3 class II β (PIK3C2β) and is not susceptible to resistance by viral mutations. M85 blocks endocytosis of influenza viruses and inhibits a broad-spectrum of viruses with minimal cytotoxicity.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Cell Line ; Chlorocebus aethiops ; Class II Phosphatidylinositol 3-Kinases/drug effects ; Disease Models, Animal ; Drug Combinations ; Drug Evaluation, Preclinical ; Drug Resistance, Viral/drug effects ; Drug Synergism ; Enzyme Inhibitors/pharmacology ; ErbB Receptors ; Female ; Humans ; Influenza A Virus, H1N1 Subtype/drug effects ; Male ; Mice ; Mice, Inbred BALB C ; Orthomyxoviridae/drug effects ; Oseltamivir/pharmacology ; Phosphatidylinositol 3-Kinases/drug effects ; Vero Cells ; Virus Internalization/drug effects
Chemical Substances	Antiviral Agents ; Drug Combinations ; Enzyme Inhibitors ; Oseltamivir (20O93L6F9H) ; Class II Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; Pik3c2b protein, mouse (EC 2.7.1.137) ; ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2019-09-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2373-8227
ISSN (online)	2373-8227
DOI	10.1021/acsinfecdis.9b00230
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Article ; Online: Protective efficacy of a plant-produced beta variant rSARS-CoV-2 VLP vaccine in golden Syrian hamsters.

Vaccine

2024 Volume 42, Issue 4, Page(s) 738–744

Abstract: In the quest for heightened protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, we engineered a prototype vaccine utilizing the plant expression system of Nicotiana benthamiana, to produce a recombinant SARS-CoV-2 ... ...

Abstract	In the quest for heightened protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, we engineered a prototype vaccine utilizing the plant expression system of Nicotiana benthamiana, to produce a recombinant SARS-CoV-2 virus-like particle (VLP) vaccine presenting the S-protein from the Beta (B.1.351) variant of concern (VOC). This innovative vaccine, formulated with either a squalene oil-in-water emulsion or a synthetic CpG oligodeoxynucleotide adjuvant, demonstrated efficacy in a golden Syrian Hamster challenge model. The Beta VLP vaccine induced a robust humoral immune response, with serum exhibiting neutralization not only against SARS-CoV-2 Beta but also cross-neutralizing Delta and Omicron pseudoviruses. Protective efficacy was demonstrated, evidenced by reduced viral RNA copies and mitigated weight loss and lung damage compared to controls. This compelling data instills confidence in the creation of a versatile platform for the local manufacturing of potential pan-sarbecovirus vaccines, against evolving viral threats.
MeSH term(s)	Animals ; Cricetinae ; Humans ; COVID-19/prevention & control ; Mesocricetus ; SARS-CoV-2 ; COVID-19 Vaccines/genetics ; Spike Glycoprotein, Coronavirus ; Antibodies, Viral ; Antibodies, Neutralizing
Chemical Substances	COVID-19 Vaccines ; Spike Glycoprotein, Coronavirus ; Antibodies, Viral ; Antibodies, Neutralizing ; spike protein, SARS-CoV-2
Language	English
Publishing date	2024-01-18
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2024.01.036
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Article: A plant-produced SARS-CoV-2 spike protein elicits heterologous immunity in hamsters.

Margolin, Emmanuel / Schäfer, Georgia / Allen, Joel D / Gers, Sophette / Woodward, Jeremy / Sutherland, Andrew D / Blumenthal, Melissa / Meyers, Ann / Shaw, Megan L / Preiser, Wolfgang / Strasser, Richard / Crispin, Max / Williamson, Anna-Lise / Rybicki, Edward P / Chapman, Ros

Frontiers in plant science

2023 Volume 14, Page(s) 1146234

Abstract: Molecular farming of vaccines has been heralded as a cheap, safe and scalable production platform. In reality, however, differences in the plant biosynthetic machinery, compared to mammalian cells, can complicate the production of viral glycoproteins. ... ...

Abstract	Molecular farming of vaccines has been heralded as a cheap, safe and scalable production platform. In reality, however, differences in the plant biosynthetic machinery, compared to mammalian cells, can complicate the production of viral glycoproteins. Remodelling the secretory pathway presents an opportunity to support key post-translational modifications, and to tailor aspects of glycosylation and glycosylation-directed folding. In this study, we applied an integrated host and glyco-engineering approach, NXS/T Generation™, to produce a SARS-CoV-2 prefusion spike trimer in
Language	English
Publishing date	2023-03-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2613694-6
ISSN	1664-462X
ISSN	1664-462X
DOI	10.3389/fpls.2023.1146234
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