Advances in respiratory virus therapeutics – A meeting report from the 6th isirv Antiviral Group conference

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Abstract

The International Society for Influenza and other Respiratory Virus Diseases held its 6th Antiviral Group (isirv-AVG) conference in Rockville, Maryland, November 13–15, 2018. The three-day program was focused on therapeutics towards seasonal and pandemic influenza, respiratory syncytial virus, coronaviruses including MERS-CoV and SARS-CoV, human rhinovirus, and other respiratory viruses. Updates were presented on several influenza antivirals including baloxavir, CC-42344, VIS410, immunoglobulin, immune plasma, MHAA4549A, pimodivir (JNJ-63623872), umifenovir, and HA minibinders; RSV antivirals including presatovir (GS-5806), ziresovir (AK0529), lumicitabine (ALS-008176), JNJ-53718678, JNJ-64417184, and EDP-938; broad spectrum antivirals such as favipiravir, VH244, remdesivir, and EIDD-1931/EIDD-2801; and host directed strategies including nitazoxanide, eritoran, and diltiazem. Other topics included considerations of novel endpoints such as ordinal scales and patient reported outcomes (PRO), and study design issues, and other regulatory considerations for antiviral drug development. The aim of this report is to provide a summary of the presentations given at this meeting.

Highlights

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Presentations given at the recent isirv-AVG conference held in Rockville, Maryland, November 13–15, 2018 are summarized.
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Viruses discussed included influenza, RSV, coronavirus including MERS-CoV and others.
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Therapeutics presented included polymerase inhibitors, fusion inhibitors, monoclonal antibodies, and host targets.
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The challenges and strategies of conducting therapeutic studies including novel endpoints were discussed.

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Most cited references 79

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The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit.

Alexandre Dias, Denis Bouvier, Thibaut Crépin … (2009)

The influenza virus polymerase, a heterotrimer composed of three subunits, PA, PB1 and PB2, is responsible for replication and transcription of the eight separate segments of the viral RNA genome in the nuclei of infected cells. The polymerase synthesizes viral messenger RNAs using short capped primers derived from cellular transcripts by a unique 'cap-snatching' mechanism. The PB2 subunit binds the 5' cap of host pre-mRNAs, which are subsequently cleaved after 10-13 nucleotides by the viral endonuclease, hitherto thought to reside in the PB2 (ref. 5) or PB1 (ref. 2) subunits. Here we describe biochemical and structural studies showing that the amino-terminal 209 residues of the PA subunit contain the endonuclease active site. We show that this domain has intrinsic RNA and DNA endonuclease activity that is strongly activated by manganese ions, matching observations reported for the endonuclease activity of the intact trimeric polymerase. Furthermore, this activity is inhibited by 2,4-dioxo-4-phenylbutanoic acid, a known inhibitor of the influenza endonuclease. The crystal structure of the domain reveals a structural core closely resembling resolvases and type II restriction endonucleases. The active site comprises a histidine and a cluster of three acidic residues, conserved in all influenza viruses, which bind two manganese ions in a configuration similar to other two-metal-dependent endonucleases. Two active site residues have previously been shown to specifically eliminate the polymerase endonuclease activity when mutated. These results will facilitate the optimisation of endonuclease inhibitors as potential new anti-influenza drugs.

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MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment

Adriaan de Wilde, V. Stalin Raj, Diede Oudshoorn … (2013)

Coronavirus (CoV) infections are commonly associated with respiratory and enteric disease in humans and animals. The 2003 outbreak of severe acute respiratory syndrome (SARS) highlighted the potentially lethal consequences of CoV-induced disease in humans. In 2012, a novel CoV (Middle East Respiratory Syndrome coronavirus; MERS-CoV) emerged, causing 49 human cases thus far, of which 23 had a fatal outcome. In this study, we characterized MERS-CoV replication and cytotoxicity in human and monkey cell lines. Electron microscopy of infected Vero cells revealed extensive membrane rearrangements, including the formation of double-membrane vesicles and convoluted membranes, which have been implicated previously in the RNA synthesis of SARS-CoV and other CoVs. Following infection, we observed rapidly increasing viral RNA synthesis and release of high titres of infectious progeny, followed by a pronounced cytopathology. These characteristics were used to develop an assay for antiviral compound screening in 96-well format, which was used to identify cyclosporin A as an inhibitor of MERS-CoV replication in cell culture. Furthermore, MERS-CoV was found to be 50–100 times more sensitive to alpha interferon (IFN-α) treatment than SARS-CoV, an observation that may have important implications for the treatment of MERS-CoV-infected patients. MERS-CoV infection did not prevent the IFN-induced nuclear translocation of phosphorylated STAT1, in contrast to infection with SARS-CoV where this block inhibits the expression of antiviral genes. These findings highlight relevant differences between these distantly related zoonotic CoVs in terms of their interaction with and evasion of the cellular innate immune response.

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Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus

Jasper F.W. Chan, Kwok-Hung Chan, Richard Kao … (2013)

Summary Objectives Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged to cause fatal infections in patients in the Middle East and traveler-associated secondary cases in Europe and Africa. Person-to-person transmission is evident in outbreaks involving household and hospital contacts. Effective antivirals are urgently needed. Methods We used small compound-based forward chemical genetics to screen a chemical library of 1280 known drugs against influenza A virus in Biosafety Level-2 laboratory. We then assessed the anti-MERS-CoV activities of the identified compounds and of interferons, nelfinavir, and lopinavir because of their reported anti-coronavirus activities in terms of cytopathic effect inhibition, viral yield reduction, and plaque reduction assays in Biosafety Level-3 laboratory. Results Ten compounds were identified as primary hits in high-throughput screening. Only mycophenolic acid exhibited low EC50 and high selectivity index. Additionally, ribavirin and interferons also exhibited in-vitro anti-MERS-CoV activity. The serum concentrations achievable at therapeutic doses of mycophenolic acid and interferon-β1b were 60–300 and 3–4 times higher than the concentrations at which in-vitro anti-MERS-CoV activities were demonstrated, whereas that of ribavirin was ∼2 times lower. Combination of mycophenolic acid and interferon-β1b lowered the EC50 of each drug by 1–3 times. Conclusions Interferon-β1b with mycophenolic acid should be considered in treatment trials of MERS.

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Author and article information

Contributors

John H. Beigel

Journal

Journal ID (nlm-ta): Antiviral Res

Journal ID (iso-abbrev): Antiviral Res

Title: Antiviral Research

Publisher: Elsevier

ISSN (Print): 0166-3542

ISSN (Electronic): 1872-9096

Publication date PMC-release: 8 April 2019

Publication date (Print): July 2019

Publication date (Electronic): 8 April 2019

Volume: 167

Pages: 45-67

Affiliations

[a ]National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

[2] ^bNorthwestern University, Feinberg School of Medicine, Chicago, IL, USA

[c ]Biomedical Advanced Research and Development Authority (BARDA), Office of the Assistant Secretary for Preparedness and Response (ASPR), Department of Health and Human Services (HHS), Washington, DC, USA

[d ]Division of Antiviral Products, Office of Antimicrobial Products, Office of New Drugs, Center for Drug Evaluation and Research, U.S Food and Drug Administration, Silver Spring, MD, USA

[e ]Gillings School of Global Public Health, Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA

Author notes

[∗ ]Corresponding author. National Institute of Allergy and Infectious Diseases (NIAID), 5601 Fishers Lane, Room 7E60, MSC 9826, Rockville, MD, 20892-9826, USA. jbeigel@ 123456niaid.nih.gov

Article

Publisher ID: S0166-3542(19)30158-5

DOI: 10.1016/j.antiviral.2019.04.006

PMC ID: 7132446

PubMed ID: 30974127

SO-VID: 40a0f1ca-bf1d-46c5-a5b1-1b9150637687

License:

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

History

Date received : 29 March 2019

Date accepted : 6 April 2019

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Advances in respiratory virus therapeutics – A meeting report from the 6th isirv Antiviral Group conference

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Abstract

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European Respiratory Society: COVID-19

Most cited references 79

The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit.

MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment

Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus

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