Lethal #mutagenesis of #RVF virus induced by #favipiravir (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Lethal mutagenesis of Rift Valley fever virus induced by favipiravir

Belén Borrego, Ana I. de Ávila, Esteban Domingo, Alejandro Brun

DOI: 10.1128/AAC.00669-19

 

ABSTRACT

Rift Valley fever virus (RVFV) is an emerging, mosquito-borne, zoonotic pathogen with recurrent outbreaks paying a considerable toll of human deaths in many African countries, for which no effective treatment is available. In cell culture studies and with laboratory animal models, the nucleoside analogue favipiravir (T-705) has demonstrated great potential for the treatment of several seasonal, chronic and emerging RNA virus infections of humans, suggesting applicability to control some viral outbreaks. Treatment with favipiravir was shown to reduce the infectivity of Rift Valley fever virus both in cell cultures and in experimental animal models, but the mechanism of this protective effect is not understood. In this work we show that favipiravir at concentrations well below the toxicity threshold estimated for cells is able to extinguish RVFV from infected cell cultures. Nucleotide sequence analysis has documented RVFV mutagenesis associated with virus extinction, with a significant increase in G to A and C to U transition frequencies, and a decrease of specific infectivity, hallmarks of lethal mutagenesis.

Copyright © 2019 Borrego et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Antivirals; Favipiravir; Arbovirus; Rift Valley fever.

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#Advances in #respiratory virus #therapeutics – A #meeting #report from the 6th isirv Antiviral Group #conference (Antiviral Res., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Antiviral Res. 2019 Apr 8. pii: S0166-3542(19)30158-5. doi: 10.1016/j.antiviral.2019.04.006. [Epub ahead of print]

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

Beigel JH1, Nam HH2, Adams PL3, Krafft A4, Ince WL5, El-Kamary SS5, Sims AC6.

Author information: 1 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address: jbeigel@niaid.nih.gov. 2 (b)Northwestern University, Feinberg School of Medicine, Chicago, IL, USA. 3 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. 4 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. 5 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. 6 Gillings School of Global Public Health, Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.

 

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.

Copyright © 2019. Published by Elsevier B.V.

KEYWORDS: Antiviral therapy; Coronavirus; Host-directed therapeutics; Influenza; Respiratory syncytial virus

PMID: 30974127 DOI: 10.1016/j.antiviral.2019.04.006

Keywords: Antivirals; Influenza A; MERS-CoV; RSV; Baloxavir; Pimodivir; Umifenovir; Favipiravir; Remdesivir; Nitazoxanide.

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#Cell line-dependent activation and #antiviral activity of T-1105, the non-fluorinated analogue of T-705 (#favipiravir) (Antiviral Res., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Antiviral Res. 2019 Apr 2. pii: S0166-3542(19)30123-8. doi: 10.1016/j.antiviral.2019.04.002. [Epub ahead of print]

Cell line-dependent activation and antiviral activity of T-1105, the non-fluorinated analogue of T-705 (favipiravir).

Huchting J1, Vanderlinden E2, Van Berwaer R3, Meier C4, Naesens L5.

Author information: 1 KU Leuven, Rega Institute for Medical Research, Herestraat 49, B-3000 Leuven, Belgium; University of Hamburg, Faculty of Sciences, Department of Chemistry, Organic Chemistry, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany. Electronic address: johanna.huchting@chemie.uni-hamburg.de. 2 KU Leuven, Rega Institute for Medical Research, Herestraat 49, B-3000 Leuven, Belgium. Electronic address: evelien.vanderlinden@kuleuven.be. 3 KU Leuven, Rega Institute for Medical Research, Herestraat 49, B-3000 Leuven, Belgium. 4 University of Hamburg, Faculty of Sciences, Department of Chemistry, Organic Chemistry, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany. Electronic address: chris.meier@chemie.uni-hamburg.de. 5 KU Leuven, Rega Institute for Medical Research, Herestraat 49, B-3000 Leuven, Belgium. Electronic address: lieve.naesens@kuleuven.be.

 

Abstract

The antiviral drug T-705 (favipiravir) and its non-fluorinated analogue T-1105 inhibit the polymerases of RNA viruses after being converted to their ribonucleoside triphosphate (RTP) metabolite. We here compared the activation efficiency of T-705 and T-1105 in four cell lines that are commonly used for their antiviral evaluation. In MDCK cells, the levels of T-705-RTP were markedly lower than those of T-1105-RTP, while the opposite was seen in A549, Vero and HEK293T cells. In the latter three cell lines, T-1105 activation was hindered by inefficient conversion of the ribonucleoside monophosphate to the ribonucleoside diphosphate en route to forming the active triphosphate. Accordingly, T-1105 had better anti-RNA virus activity in MDCK cells, while T-705 was more potent in the other three cell lines. Additionally, we identified a fourth metabolite, the NAD analogue of T-705/T-1105, and showed that it can be formed by nicotinamide mononucleotide adenylyltransferase.

Copyright © 2019. Published by Elsevier B.V.

KEYWORDS: Activation; Antiviral; Cell line dependency; Favipiravir; Nicotinamide mononucleotide analogue

PMID: 30951731 DOI: 10.1016/j.antiviral.2019.04.002

Keywords: Antivirals; Favipiravir.

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#Inhibition of #avian-origin #influenza A(#H7N9) virus by the novel cap-dependent endonuclease inhibitor #baloxavir marboxil (Sci Rep., abstract)

[Source: Scientific Reports, full page: (LINK). Abstract, edited.]

Inhibition of avian-origin influenza A(H7N9) virus by the novel cap-dependent endonuclease inhibitor baloxavir marboxil

Keiichi Taniguchi, Yoshinori Ando, Haruaki Nobori, Shinsuke Toba, Takeshi Noshi, Masanori Kobayashi, Makoto Kawai, Ryu Yoshida, Akihiko Sato, Takao Shishido, Akira Naito, Keita Matsuno, Masatoshi Okamatsu, Yoshihiro Sakoda & Hiroshi Kida

Scientific Reports, volume 9, Article number: 3466 (2019)

 

Abstract

Human infections with avian-origin influenza A(H7N9) virus represent a serious threat to global health; however, treatment options are limited. Here, we show the inhibitory effects of baloxavir acid (BXA) and its prodrug baloxavir marboxil (BXM), a first-in-class cap-dependent endonuclease inhibitor, against A(H7N9), in vitro and in vivo. In cell culture, BXA at four nanomolar concentration achieved a 1.5–2.8 log reduction in virus titers of A(H7N9), including the NA-R292K mutant virus and highly pathogenic avian influenza viruses, whereas NA inhibitors or favipiravir required approximately 20-fold or higher concentrations to achieve the same levels of reduction. A(H7N9)-specific amino acid polymorphism at position 37, implicated in BXA binding to the PA endonuclease domain, did not impact on BXA susceptibility. In mice, oral administration of BXM at 5 and 50 mg/kg twice a day for 5 days completely protected from a lethal A/Anhui/1/2013 (H7N9) challenge, and reduced virus titers more than 2–3 log in the lungs. Furthermore, the potent therapeutic effects of BXM in mice were still observed when a higher virus dose was administered or treatment was delayed up to 48 hours post infection. These findings support further investigation of BXM for A(H7N9) treatment in humans.

Keywords: Avian Influenza; H7N9; Antivirals; Baloxavir marboxil; Favipiravir.

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#Laboratory #findings, compassionate use of #favipiravir, and outcome in patients with #Ebola virus disease, #Guinea, 2015 – a retrospective observational study (J Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Infect Dis. 2019 Feb 21. pii: jiz078. doi: 10.1093/infdis/jiz078. [Epub ahead of print]

Laboratory findings, compassionate use of favipiravir, and outcome in patients with Ebola virus disease, Guinea, 2015 – a retrospective observational study.

Kerber R1,2,3, Lorenz E1,3, Duraffour S1,2,3, Sissoko D4,5, Rudolf M1,2,3, Jaeger A1,3, Cisse SD6, Camara AM6, Miranda O7, Castro CM7, Akoi Bore J2,6, Raymond Koundouno F2,6, Repits J2,8, Afrough B2,9, Becker-Ziaja B1,2,3, Hinzmann J2,10, Mertens M2,3,11, Vitoriano I2,9, Hugh Logue C2,9, Böttcher JP2,10, Pallasch E1,2,3, Sachse A2,10, Bah A2,12, Cabeza-Cabrerizo M2, Nitzsche K2, Kuisma E2,9, Michel J2,10, Holm T1,2,3, Gayle Zekeng E2, Cowley LA2,13,14, Garcia-Dorival I2,15, Hetzelt N2,10, Josef Baum JH1,2, Portmann J2,16, Carter L2,17,18, Yenamaberhan RL1,2, Camino A2, Enkirch T2,19, Singethan K2,20, Meisel S1,2, Mazzarelli A2,21, Kosgei A2,22, Kafetzopoulou L2,23, Rickett NY2,15, Patrono LV1,2, Ghebreghiorghis L2,10, Arnold U2,10, Colin G4,5,24, Juchet S4,5,24, Marchal CL4, Kolie JS25, Beavogui AH25, Wurr S1,2,3, Bockholt S1,2,3, Krumkamp R1,3, May J1,3, Stoecker K2,3,26, Fleischmann E2,3,26, Ippolito G2,21, W Carroll M2,9,27, Koivogui L28, Magassouba N29, Keita S6, Gurry C18, Drury P18, Diallo B30, Formenty P18, Wölfel R2,3,26, Caro AD2,21, Gabriel M1,2,3, Anglaret X4,5,24, Malvy D4,5, Günther S1,2,3.

Author information: 1 Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany. 2 The European Mobile Laboratory Consortium, Hamburg, Germany. 3 German Centre for Infection Research (DZIF), Germany. 4 INSERM U1219, Bordeaux University, Bordeaux, France. 5 Bordeaux University Hospital, Bordeaux, France. 6 Ministry of Health Guinea, Conakry, Guinea. 7 Hospital Militar Central Dr. Carlos J. Finlay, Havana, Cuba. 8 Janssen-Cilag, Sollentuna, Sweden. 9 Public Health England, Porton Down, Salisbury, United Kingdom. 10 Robert Koch Institute, Berlin, Germany. 11 Friedrich Loeffler Institute, Federal Research Institute for Animal Health, Greifswald, Insel Riems, Germany. 12 Swiss Tropical and Public Health Institute, Basel, Switzerland. 13 Public Health England, London, United Kingdom. 14 The Milner Centre for Evolution, University of Bath, Bath, United Kingdom. 15 Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom. 16 Federal Office for Civil Protection, Spiez Laboratory, Spiez, Switzerlands. 17 University College London, London, United Kingdom. 18 World Health Organization, Geneva, Switzerland. 19 Paul-Ehrlich-Institut, Division of Veterinary Medicine, Langen, Germany. 20 Institute of Virology, Technische Universität München, Munich, Germany. 21 National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, Rome, Italy. 22 Kenya Medical Research Institute, Nairobi, Kenya. 23 KU Leuven – University of Leuven, Rega Institute for Medical Research, Leuven, Belgium. 24 PAC-CI, ANRS Research Site, Treichville University Hospital, Abidjan, Côte d’Ivoire. 25 Centre de Recherche en Santé Rurale, Maférinya, Guinea. 26 Bundeswehr Institute of Microbiology, Munich, Germany. 27 University of Southampton, South General Hospital, Southampton, United Kingdom. 28 Institut National de Santé Publique, Conakry, Guinea. 29 Université Gamal Abdel Nasser de Conakry, Laboratoire des Fièvres Hémorragiques en Guinée, Conakry, Guinea. 30 World Health Organization, Conakry, Guinea.

 

Abstract

BACKGROUND:

In 2015, the laboratory at the Ebola treatment center in Coyah, Guinea, confirmed Ebola virus disease (EVD) in 286 patients. Cycle threshold (Ct) in the Ebola virus RT-PCR and 13 blood chemistry parameters were measured on admission and during hospitalization. Favipiravir treatment was offered to EVD patients on compassionate use basis.

METHODS:

To reduce biases in the raw field data, we carefully selected 163 of the 286 EVD patients for a retrospective study to assess associations between potential risk factors, alterations in blood chemistry, favipiravir treatment, and outcome.

RESULTS:

The case fatality rate in favipiravir-treated patients was lower than in untreated patients (31/73 [42.5%] vs. 52/90 [57.8%], p = 0.053 in univariate analysis). In the multivariate regression analysis, higher Ct value and younger age were associated with survival (p <0.001), while favipiravir treatment showed no statistically significant effect (p = 0.11). However, Kaplan-Meier analysis indicated a longer survival time in the favipiravir-treated group (p = 0.015). The study also showed characteristic changes in blood chemistry in fatal cases vs. survivors.

CONCLUSIONS:

Consistent with the JIKI trial, this retrospective study reveals a trend toward improved survival in favipiravir-treated patients; however, the effect was not statistically significant except for survival time.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.

KEYWORDS: Ebola virus disease; Epidemic; Favipiravir; Filovirus; Guinea; Mobile laboratory

PMID: 30788508 DOI: 10.1093/infdis/jiz078

Keywords: Ebola; Ebola-Makona; Guinea; Antivirals; Favipiravir.

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#AZT acts as an anti- #influenza nucleotide triphosphate targeting the catalytic site of A/PR/8/34/ #H1N1 RNA dependent RNA #polymerase (J Comput Aided Mol Des., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Comput Aided Mol Des. 2019 Feb 9. doi: 10.1007/s10822-019-00189-w. [Epub ahead of print]

AZT acts as an anti-influenza nucleotide triphosphate targeting the catalytic site of A/PR/8/34/H1N1 RNA dependent RNA polymerase.

Pagadala NS1,2,3,4.

Author information: 1 Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada. nattu251@gmail.com. 2 Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, AB, Canada. nattu251@gmail.com. 3 Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada. nattu251@gmail.com. 4 Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, T6G 2E1, Canada. nattu251@gmail.com.

 

Abstract

To develop potent drugs that inhibit the activity of influenza virus RNA dependent RNA polymerase (RdRp), a set of compounds favipiravir, T-705, T-1105 and T-1106, ribavirin, ribavirin triphosphate viramidine, 2FdGTP (2′-deoxy-2′-fluoroguanosine triphosphate) and AZT-TP (3′-Azido-3′-deoxy-thymidine-5′-triphosphate) were docked with a homology model of IAV RdRp from the A/PR/8/34/H1N1 strain. These compounds bind to four pockets A-D of the IAV RdRp with different mechanism of action. In addition, AZT-TP also binds to the PB1 catalytic site near to the tip of the priming loop with a highest ΔG of - 16.7 Kcal/mol exhibiting an IC50 of 1.12 µM in an in vitro enzyme transcription assay. This shows that AZT-TP mainly prevents the incorporation of incoming nucleotide involved in initiation of vRNA replication. Conversely, 2FdGTP used as a positive control binds to pocket-B at the end of tunnel-II with a highest ΔG of - 16.3 Kcal/mol inhibiting chain termination with a similar IC50 of 1.12 µM. Overall, our computational results in correlation with experimental studies gives information for the first time about the binding modes of the known influenza antiviral compounds in different models of vRNA replication by IAV RdRp. This in turn gives new structural insights for the development of new therapeutics exhibiting high specificity to the PB1 catalytic site of influenza A viruses.

KEYWORDS: Catalytic site; Docking; Nucleotide triphosphates; RNA dependent RNA polymerase

PMID: 30739239 DOI: 10.1007/s10822-019-00189-w

Keywords: Influenza A; H1N1; Antivirals; AZT; Ribavirin; Favipiravir.

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#Filovirus #Virulence in #Interferon α/β and γ Double Knockout Mice, and #Treatment with #Favipiravir (Viruses, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Viruses. 2019 Feb 3;11(2). pii: E137. doi: 10.3390/v11020137.

Filovirus Virulence in Interferon α/β and γ Double Knockout Mice, and Treatment with Favipiravir.

Comer JE1,2,3,4, Escaffre O5, Neef N6, Brasel T7,8,9, Juelich TL10, Smith JK11, Smith J12, Kalveram B13, Perez DD14, Massey S15, Zhang L16, Freiberg AN17,18,19,20.

Author information: 1 Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jscomer@UTMB.edu. 2 Office of Regulated Nonclinical Studies, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jscomer@UTMB.edu. 3 Sealy Institute for Vaccine Science, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jscomer@UTMB.edu. 4 The Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jscomer@UTMB.edu. 5 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. olescaff@utmb.edu. 6 Experimental Pathology Laboratories, Inc., Sterling, VA 20167, USA. nneef@7thwavelabs.com. 7 Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. trbrasel@utmb.edu. 8 Office of Regulated Nonclinical Studies, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. trbrasel@utmb.edu. 9 Sealy Institute for Vaccine Science, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. trbrasel@utmb.edu. 10 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. tljuelic@utmb.edu. 11 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jeksmith@UTMB.EDU. 12 Office of Regulated Nonclinical Studies, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. jensmit1@utmb.edu. 13 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. bkkalver@utmb.edu. 14 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. dadperez@tamu.edu. 15 Office of Regulated Nonclinical Studies, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. chmassey@utmb.edu. 16 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. lihzhang@utmb.edu. 17 Sealy Institute for Vaccine Science, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. anfreibe@utmb.edu. 18 The Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. anfreibe@utmb.edu. 19 Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. anfreibe@utmb.edu. 20 Institute for Human Infections and Immunity, University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA. anfreibe@utmb.edu.

 

Abstract

The 2014 Ebolavirus outbreak in West Africa highlighted the need for vaccines and therapeutics to prevent and treat filovirus infections. A well-characterized small animal model that is susceptible to wild-type filoviruses would facilitate the screening of anti-filovirus agents. To that end, we characterized knockout mice lacking α/β and γ interferon receptors (IFNAGR KO) as a model for wild-type filovirus infection. Intraperitoneal challenge of IFNAGR KO mice with several known human pathogenic species from the genus Ebolavirus and Marburgvirus, except Bundibugyo ebolavirus and Taï Forest ebolavirus, caused variable mortality rate. Further characterization of the prototype Ebola virus Kikwit isolate infection in this KO mouse model showed 100% lethality down to a dilution equivalent to 1.0 × 10-1 pfu with all deaths occurring between 7 and 9 days post-challenge. Viral RNA was detectable in serum after challenge with 1.0 × 10² pfu as early as one day after infection. Changes in hematology and serum chemistry became pronounced as the disease progressed and mirrored the histological changes in the spleen and liver that were also consistent with those described for patients with Ebola virus disease. In a proof-of-principle study, treatment of Ebola virus infected IFNAGR KO mice with favipiravir resulted in 83% protection. Taken together, the data suggest that IFNAGR KO mice may be a useful model for early screening of anti-filovirus medical countermeasures.

KEYWORDS: Ebola virus; filovirus; interferon receptor knockout; mouse

PMID: 30717492 DOI: 10.3390/v11020137 Free full text

Keywords: Filovirus; Ebola; Marburg; Ebola Bundibugyo; Tai Forest Virus; Favipiravir; Antivirals; Animal models.

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