DOCSLIB.ORG

Single-Stranded Oligonucleotide-Mediated Inhibition of Respiratory Syncytial Virus Infection

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Single-Stranded Oligonucleotide-Mediated Inhibition of Respiratory Syncytial Virus Infection Single-Stranded Oligonucleotide-mediated Inhibition of Respiratory Syncytial Virus Infection Axberg Palsson, S., Dondalska, A., Bergenstrahle, J. A., Rolfes, C., Bjork, A., Sedano, L., Power, U., Remeix- Welti, M-A., Mastrangelo, P., Eleouet, J-F., Le Goffic, R., Galloux, M., & Spetz, A-L. (2020). Single-Stranded Oligonucleotide-mediated Inhibition of Respiratory Syncytial Virus Infection. Frontiers in immunology, 11, [580547]. https://doi.org/10.3389/fimmu.2020.580547 Published in: Frontiers in immunology Document Version: Publisher's PDF, also known as Version of record Queen's University Belfast - Research Portal: Link to publication record in Queen's University Belfast Research Portal Publisher rights Copyright 2020 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. General rights Copyright for the publications made accessible via the Queen's University Belfast Research Portal is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The Research Portal is Queen's institutional repository that provides access to Queen's research output. Every effort has been made to ensure that content in the Research Portal does not infringe any person's rights, or applicable UK laws. If you discover content in the Research Portal that you believe breaches copyright or violates any law, please contact [email protected]. Download date:25. Sep. 2021 ORIGINAL RESEARCH published: 08 December 2020 doi: 10.3389/fimmu.2020.580547 Single-Stranded Oligonucleotide- Mediated Inhibition of Respiratory Syncytial Virus Infection Sandra Axberg Pålsson 1*, Aleksandra Dondalska 1, Joseph Bergenstråhle 2, Caroline Rolfes 1, Albin Björk 3, Laura Sedano 4, Ultan F. Power 5, Marie-Anne Rameix-Welti 6, Joakim Lundeberg 2, Marie Wahren-Herlenius 3, 7 4 4 4 Edited by: Peter Mastrangelo , Jean-Francois Eleouet , Ronan Le Goffic , Marie Galloux 1 Aurelio Cafaro, and Anna-Lena Spetz * National Institute of Health (ISS), Italy 1 Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden, 2 Science for Reviewed by: Life Laboratory, Department of Gene Technology, Royal Institute of Technology, Stockholm, Sweden, 3 Division of Michael Teng, Rheumatology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden, 4 UR0892 University of South Florida, Unite´ VIM, INRAE, Universite´ Paris-Saclay, Jouy-en-Josas, France, 5 Wellcome-Wolfson Institute for Experimental Medicine, United States School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, Northern Ireland, 6 UMR INSERM Nicolas Cuburu, U1173 I2, UFR des Sciences de la Sante´ Simone Veil—UVSQ, Montigny-Le-Bretonneux, France, 7 Department of Laboratory National Cancer Institute (NCI), Medicine and Pathobiology, University of Toronto, Toronto, Canada United States *Correspondence: Sandra Axberg Pålsson Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract [email protected] infections in young children. Currently, there is no RSV vaccine or universally accessible Anna-Lena Spetz [email protected] antiviral treatment available. Addressing the urgent need for new antiviral agents, we have investigated the capacity of a non-coding single-stranded oligonucleotide (ssON) to inhibit Specialty section: RSV infection. By utilizing a GFP-expressing RSV, we demonstrate that the ssON This article was submitted to significantly reduced the proportion of RSV infected A549 cells (lung epithelial cells). Viral Immunology, a section of the journal Furthermore, we show that ssON’s antiviral activity was length dependent and that both Frontiers in Immunology RNA and DNA of this class of oligonucleotides have antiviral activity. We reveal that ssON Received: 06 July 2020 inhibited RSV infection by competing with the virus for binding to the cellular receptor Accepted: 09 November 2020 Published: 08 December 2020 nucleolin in vitro. Additionally, using a recombinant RSV that expresses luciferase we Citation: show that ssON effectively blocked RSV infection in mice. Treatment with ssON in vivo Pålsson SA, Dondalska A, resulted in the upregulation of RSV-induced interferon stimulated genes (ISGs) such as Bergenstråhle J, Rolfes C, Björk A, Stat1, Stat2, Cxcl10,andCcl2. This study highlights the possibility of using Sedano L, Power UF, Rameix-Welti M-A, Lundeberg J, Wahren-Herlenius M, oligonucleotides as therapeutic agents against RSV infection. We demonstrate that the Mastrangelo P, Eleouet J-F, mechanism of action of ssON is the inhibition of viral entry in vitro, likely through the Le GofficR,Galloux M and Spetz A-L (2020) Single-Stranded binding of the receptor, nucleolin and that ssON treatment against RSV infection in vivo Oligonucleotide-Mediated Inhibition of additionally results in the upregulation of ISGs. Respiratory Syncytial Virus Infection. Front. Immunol. 11:580547. Keywords: respiratory syncytial virus (RSV), oligonucleotides, single-stranded oligonucleotides, ssON, antiviral, doi: 10.3389/fimmu.2020.580547 nucleolin, ISGs Frontiers in Immunology | www.frontiersin.org 1 December 2020 | Volume 11 | Article 580547 Pålsson et al. Oligonucleotide-Mediated Inhibition of RSV infection INTRODUCTION shown to inhibit clathrin- and caveolin-mediated endocytosis (11), could inhibit RSV infection. We evaluated anti-RSV activity Human respiratory syncytial virus (RSV) is a negative sense single- against a RSV-A virus expressing GFP (RSV-GFP) by assessing stranded RNA virus of the Pneumoviridae family. It causes acute the proportion of A549 infected cells using flow cytometry severe infections in the lower respiratory tract of children, the elderly (Supplementary Figure 1, gating strategy). Pre-treatment with and immunocompromised individuals (1). Annually, 64 million cases ssON or concomitant addition of ssON and RSV to A549 cells of RSV infection are reported globally and of these, approximately resulted in a significantly reduced proportion of GFP positive 160,000 cases result in death (National Institute of Allergy and RSV-infected cells (~10%) (Figure 1A) as compared to the RSV- Infectious Diseases; https://www.niaid.nih.gov). Furthermore, reports infected untreated controls (~60%). indicate that 90% of children are infected with RSV within their first We next evaluated ssON´s anti-RSV activity using MOIs two years of life (2). In addition, the development of wheezing and ranging from 0.01 to 1 (Figure 1B). We found that ssON asthma have been associated with early-life RSV infection (3). effectively blocked RSV infection for all MOIs assessed There is currently no RSV-specific antiviral treatment or vaccine regardless of whether ssON was added before infection or against RSV, except for an immunoprophylactic anti-RSV monoclonal simultaneously with the virus (Figure 1B). The antiviral antibody (Palivizumab) or intravenous immunoglobulin (IVIG) activity persisted for up to 96h after a single ssON exposure. treatment. Unfortunately, due to high cost, use of Palivizumab is We also monitored cell viability and found that the highest RSV restricted to children at a high risk of developing severe RSV-induced infection dose (MOI 1) resulted in increased cell death overtime disease, such as premature infants, immunocompromised newborn (~10-30%). Notably, neither pre-incubation nor concomitant babies, or children with congenital heart or lung disease, in high addition of ssON and RSV negatively affected the viability of income countries (4, 5). Although several ongoing clinical studies are A549 cells. Instead, there was a clear trend that ssON treatment exploring potential RSV vaccines and new anti-RSV monoclonal reduced the cell death by up to 25% in the cell cultures exposed to antibodies, successful progress has been slow. In parallel, many the highest MOI 1 (Figure 1C). recent studies are focusing on the development of alternative RSV We have previously reported that the capability of ssONs to inhibitors and the pipeline of new anti-RSV therapeutics was recently interfere with endocytosis is dependent on the length of the reviewed (6). Examples of new antiviral compounds are the fusion oligonucleotide. Oligonucleotides with the same lengths as inhibitors Presatovir (GS-5806), TMC353121 and JNJ-678, and miRNAs do not possess this feature. However, somewhat replication inhibitors such as Lumicitabine (ALS-8176) (7). longer oligonucleotides of at least 25 bases may exert such RSV was shown to enter ciliated epithelial cells via receptor- activity (11). The endocytosis inhibitory capacity is not based mediated endocytosis, utilizing nucleolin as a possible cellular receptor on complementary binding to another oligonucleotide but for viral entry (8). However, emerging studies indicate that RSV is requires certain structural features to have this activity (11). In taken up via macropinocytosis rather than endocytosis (9, 10). Hence, addition, there is extensive data in the literature that the chemical a detailed route of RSV infection remains to be further elucidated and phosphorothioate (PS) modification of the backbone prolongs entry is likely to involve a multimeric protein complex. Here, we the half-life of the oligonucleotides
Load more

Recommended publications
  • Optumrx Brand Pipeline Forecast
    RxOutlook® 1st Quarter 2019 OptumRx brand pipeline forecast Route of Regulatory Estimated Specialty Orphan Drug name Generic name Company Drug class Therapeutic use administration status release date drug drug 2019 Possible launch date Ophthalmological DS-300 DS-300 Eton undisclosed SC Filed NDA 2019 unknown N disease anti-sclerostin Evenity romosozumab Amgen Osteoporosis SC Filed NDA 2/2019 Y N monoclonal antibody tetrahydrofolate iclaprim iclaprim Motif Bio Bacterial infections IV Filed NDA 2/13/2019 Y Y dehydrogenase inhibitor tazarotene/ IDP-118 Valeant retinoid/ corticosteroid Psoriasis TOP Filed NDA 2/15/2019 N N halobetasol adenosine deaminase Mavenclad cladribine Merck/ Teva resistant Multiple sclerosis PO Filed NDA 2/15/2019 Y N deoxyadenosine analog Lotemax Gel loteprednol Valeant corticosteroid Ocular inflammation OP Filed NDA 2/25/2019 N N Nex Gen etabonate turoctocog alfa glyco-PEGylated factor NN-7088 Novo Nordisk Hemophilia IV/SC Filed BLA 2/27/2019 Y N pegol VIII derivative selective sphingosine-1 BAF-312 siponimod Novartis phosphate receptor Multiple sclerosis PO Filed NDA 3/1/2019 Y N agonist midazolam midazolam UCB benzodiazepine Seizures Intranasal Filed NDA 3/1/2019 N Y (USL-261) XeriSol glucagon Xeris glucagon analog Diabetes mellitus SC Filed NDA 3/1/2019 N N Glucagon optum.com/optumrx 1 RxOutlook® 1st Quarter 2019 Route of Regulatory Estimated Specialty Orphan Drug name Generic name Company Drug class Therapeutic use administration status release date drug drug dopamine receptor JZP-507 sodium oxybate Jazz Narcolepsy
    [Show full text]
  • Microorganisms-07-00521-V2.Pdf
    microorganisms Review Are Community Acquired Respiratory Viral Infections an Underestimated Burden in Hematology Patients? Cristian-Marian Popescu 1,* , Aurora Livia Ursache 2, Gavriela Feketea 1 , Corina Bocsan 3, Laura Jimbu 1, Oana Mesaros 1, Michael Edwards 4,5, Hongwei Wang 6, Iulia Berceanu 7, Alexandra Neaga 1 and Mihnea Zdrenghea 1,7,* 1 Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes str., 400012 Cluj-Napoca, Romania; [email protected] (G.F.); [email protected] (L.J.); [email protected] (O.M.); [email protected] (A.N.) 2 The Faculty of Veterinary Medicine, University of Agricultural Sciences and Veterinary Medicine, Calea Mănăs, tur 3-5, 400372 Cluj-Napoca, Romania; [email protected] 3 Department of Pharmacology, Toxicology and Clinical Pharmacology, Iuliu Ha¸tieganuUniversity of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania; [email protected] 4 National Heart and Lung Institute, St Mary’s Campus, Imperial College London, London W2 1PG, UK; [email protected] 5 Medical Research Council (MRC) and Asthma UK Centre in Allergic Mechanisms of Asthma, London W2 1PG, UK 6 School of Medicine, Nanjing University, 22 Hankou Road, Nanjing 210093, China; [email protected] 7 Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania; [email protected] * Correspondence: [email protected] (C.-M.P.); [email protected] (M.Z.) Received: 8 October 2019; Accepted: 31 October 2019; Published: 2 November 2019 Abstract: Despite a plethora of studies demonstrating significant morbidity and mortality due to community-acquired respiratory viral (CRV) infections in intensively treated hematology patients, and despite the availability of evidence-based guidelines for the diagnosis and management of respiratory viral infections in this setting, there is no uniform inclusion of respiratory viral infection management in the clinical hematology routine.
    [Show full text]
  • Drug Repurposing for Identification of Potential Inhibitors Against SARS-Cov-2 Spike Receptor-Binding Domain: an in Silico Approach
    Indian J Med Res 153, January & February 2021, pp 132-143 Quick Response Code: DOI: 10.4103/ijmr.IJMR_1132_20 Drug repurposing for identification of potential inhibitors against SARS-CoV-2 spike receptor-binding domain: An in silico approach Santosh Kumar Behera1, Namita Mahapatra1, Chandra Sekhar Tripathy1 & Sanghamitra Pati2 1Health Informatics Centre, 2ICMR-Regional Medical Research Centre, Bhubaneswar, Odisha, India Received April 10, 2020 Background & objectives: The world is currently under the threat of coronavirus disease 2019 (COVID-19) infection, caused by SARS-CoV-2. The objective of the present investigation was to repurpose the drugs with potential antiviral activity against receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein among 56 commercially available drugs. Therefore, an integrative computational approach, using molecular docking, quantum chemical calculation and molecular dynamics, was performed to unzip the effective drug-target interactions between RBD and 56 commercially available drugs. Methods: The present in silico approach was based on information of drugs and experimentally derived crystal structure of RBD of SARS-CoV-2 S protein. Molecular docking analysis was performed for RBD against all 56 reported drugs using AutoDock 4.2 tool to screen the drugs with better potential antiviral activity which were further analysed by other computational tools for repurposing potential drug or drugs for COVID-19 therapeutics. Results: Drugs such as chalcone, grazoprevir, enzaplatovir, dolutegravir, daclatasvir, tideglusib, presatovir, remdesivir and simeprevir were predicted to be potentially effective antiviral drugs against RBD and could have good COVID-19 therapeutic efficacy. Simeprevir displayed the highest binding affinity and reactivity against RBD with the values of −8.52 kcal/mol (binding energy) and 9.254 kcal/mol (band energy gap) among all the 56 drugs under investigation.
    [Show full text]
  • Development of Novel Anti-Respiratory Syncytial Virus Therapies
    Development of Novel Anti-Respiratory Syncytial Virus Therapies by Michael J Norris A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Laboratory Medicine and Pathobiology University of Toronto © Copyright by Michael J Norris 2017 Development of Novel Anti-Respiratory Syncytial Virus Therapies Michael J Norris Doctor of Philosophy Laboratory Medicine and Pathobiology University of Toronto 2017 Abstract Respiratory syncytial virus (RSV) is a leading cause of mortality in infants and young children. Despite the RSV disease burden, no vaccine is available and treatment remains non-specific. New drug candidates are needed to combat RSV. Towards this goal, we investigated two broad strategies to control RSV infection. First, we examined the utility of delivering an anti-4-1BB agonist antibody to enhance CD8 T cell costimulation in a mouse model of RSV infection. This strategy enhanced CD8 T cell numbers, however failed to reduce RSV titers in the lung. We found that this was likely due to reduced RSV specific CD8 T cells in the lung. Overall, this strategy did not attenuate RSV associated disease outcomes and was associated with increased morbidity. Second, we screened over 2000 FDA approved compounds to identify approved drugs with novel anti-RSV activity. Cardiac glycosides, inhibitors of the membrane bound Na+/K+-ATPase, were identified to have anti-RSV activity. Cardiac glycosides diminished RSV infection in HEp-2 cells and in primary human airway epithelial cells grown at an air liquid interface. Digoxin, an FDA approved cardiac glycoside, was further able to inhibit RSV infection of community isolates of RSV in primary nasal epithelial cells.
    [Show full text]
  • Communication DOI: 10.5582/Ddt.2020.01012
    58 Drug Discoveries & Therapeutics. 2020; 14(1):58-60. Communication DOI: 10.5582/ddt.2020.01012 Discovering drugs to treat coronavirus disease 2019 (COVID-19) Liying Dong1, Shasha Hu2, Jianjun Gao1,* 1 Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, Shandong, China; 2 Department of Pathology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China. SUMMARY The SARS-CoV-2 virus emerged in December 2019 and then spread rapidly worldwide, particularly to China, Japan, and South Korea. Scientists are endeavoring to find antivirals specific to the virus. Several drugs such as chloroquine, arbidol, remdesivir, and favipiravir are currently undergoing clinical studies to test their efficacy and safety in the treatment of coronavirus disease 2019 (COVID-19) in China; some promising results have been achieved thus far. This article summarizes agents with potential efficacy against SARS-CoV-2. Keywords novel coronavirus, pneumonia, COVID-19, 2019-nCoV, SARS-CoV-2 The virus SARS-CoV-2 (formerly designated 2019- day. Ribavirin should be administered via intravenous nCoV) emerged in December 2019 and then spread infusion at a dose of 500 mg for adults, 2 to 3 times/ rapidly worldwide, particularly to China, Japan, and day in combination with IFN-α or lopinavir/ritonavir. South Korea. As of February 21, 2020, a total of Chloroquine phosphate is orally administered at a dose 76,288 confirmed cases of coronavirus disease 2019 of 500 mg (300 mg for chloroquine) for adults, 2 times/ (COVID-19) and 2,345 deaths have been reported in day. Arbidol is orally administered at a dose of 200 mg mainland China (1).
    [Show full text]
  • RSV in the Elderly. Troubled Past, Dark Present, Bright Future?
    RSV infection in the elderly troubled past, dark present, bright future ? Nicolas Dauby MD, PhD, Infectious Diseases Department - CHU Saint Pierre 4th April 2019 – SBIMC-SBP-BSGG Symposium In collaboration with Valérie Martinet MD, PhD, Geriatrics, CHU Saint Pierre Outline 1. Introduction 2. Mechanisms of RSV disease in elderly 3. Epidemiology and burden 4. Future therapeutical intervention 5. Prevention : vaccination Respiratory syncytial virus (RSV) • Discovered in 1956 • Enveloped RNA virus • Common & ubiquitous respiratory virus • North hemisphere : Annual epidemics during the cold season (nov-march) • A & B subtypes Seasonality of RSV infection Alberta, Canada 2008-2015 Proportion of RSV positive assay by luminex Assay Griffiths CMR 2017 Age as a major determinant of RSV disease Most common respiratory infection in infants 95% infected before 2 years Openshaw Annual Rev Immunol 2017 1. Introduction 2. Mechanisms of RSV disease in elderly 3. Epidemiology and burden 4. Future therapeutical intervention 5. Prevention : vaccination Pathways leading to antiviral defense & immunopathology during RSV infection Protective vs Harmful immunity Openshaw, Annual Rev Immunol 2017 Impact of aging on systemic immune functions Defective phagocytosis Defective phagocytosis Reduced functions Inflammaging Lower effector functions Reduced proliferation The ageing lung Alveolar epithelial cells Pro-Inf. Cytokines Neutrophils Functionality Bowdish Chest 2019 Mechanisms of diseases in the elderly • Lower frequency of RSV-specific CD8 T cells – Associated
    [Show full text]
  • WO 2016/022464 Al 11 February 2016 (11.02.2016) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/022464 Al 11 February 2016 (11.02.2016) P O P C T (51) International Patent Classification GELMAN, Leonid; 260 E. Grand Avenue, 2nd Floor, A61K 31/7068 (2006.01) A61K 31/519 (2006.01) South San Francisco, CA 94080 (US). SMITH, David, A61K 31/4184 (2006.01) A61K 31/166 (2006.01) Bernard; 260 E. Grand Avenue, 2nd Floor, South San A61K 31/675 (2006.01) A61K 31/41 (2006.01) Francisco, CA 94080 (US). WANG, Guangyi; 260 E. A61K 31/513 (2006.01) A61K 38/21 (2006.01) Grand Avenue, 2nd Floor, South San Francisco, CA 94080 A61K 31/506 (2006.01) A61K 38/16 (2006.01) (US). A61K 31/437 (2006.01) A61K 39/155 (2006.01) (74) Agent: MILLER, Kimberly, J.; Knobbe Martens Olson A61K 31/4709 (2006.01) A61K 39/42 (2006.01) & Bear, LLP, 2040 Main Street, 14th Floor, Irvine, CA A61K 31/4188 (2006.01) A61P 31/14 (2006.01) 92614 (US). A61K 31/517 (2006.01) A61P 11/00 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: PCT/US20 15/043402 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (22) International Filing Date: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 3 August 2015 (03.08.2015) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, English (25) Filing Language: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (26) Publication Language: English MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (30) Priority Data: SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 62/033,55 1 5 August 2014 (05.08.2014) US TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
    [Show full text]
  • Respiratory Syncytial Virus Entry and How to Block It
    REVIEWS Respiratory syncytial virus entry and how to block it Michael B. Battles1 and Jason S. McLellan 2* Abstract | Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease in young children and elderly people. Although the virus was isolated in 1955, an effective RSV vaccine has not been developed, and the only licensed intervention is passive immunoprophylaxis of high-risk infants with a humanized monoclonal antibody. During the past 5 years, however, there has been substantial progress in our understanding of the structure and function of the RSV glycoproteins and their interactions with host cell factors that mediate entry. This period has coincided with renewed interest in developing effective interventions, including the isolation of potent monoclonal antibodies and small molecules and the design of novel vaccine candidates. In this Review , we summarize the recent findings that have begun to elucidate RSV entry mechanisms, describe progress on the development of new interventions and conclude with a perspective on gaps in our knowledge that require further investigation. Nasopharynx Respiratory syncytial virus (RSV) was first isolated increase mucus production and inflammation, leading The upper part of the pharynx in 1955 from chimpanzees suffering from respiratory to a narrowing of the airway that results in bronchiolitis that connects with the nasal illness at the Walter Reed Army Institute of Research in young children and acute respiratory illness in older cavity. in the United States1. In the following years, the virus adults or those with underlying chronic conditions13. Bronchioles was also isolated from infants with severe lower respira- During a series of clinical trials in the 1960s, aberrant 2,3 Small tubes in the lung through tory illness .
    [Show full text]
  • 2019 Icar Program & Abstracts Book
    Hosted by the International Society for Antiviral Research (ISAR) ND International Conference 32on Antiviral Research (ICAR) Baltimore MARYLAND PROGRAM and USA Hyatt Regency BALTIMORE ABSTRACTS May 12-15 2019 ND TABLE OF International Conference CONTENTS 32on Antiviral Research (ICAR) Daily Schedule . .3 Organization . 4 Contributors . 5 Keynotes & Networking . 6 Schedule at a Glance . 7 ISAR Awardees . 10 The 2019 Chu Family Foundation Scholarship Awardees . 15 Speaker Biographies . 17 Program Schedule . .25 Posters . 37 Abstracts . 53 Author Index . 130 PROGRAM and ABSTRACTS of the 32nd International Conference on Antiviral Research (ICAR) 2 ND DAILY International Conference SCHEDULE 32on Antiviral Research (ICAR) SUNDAY, MAY 12, 2019 › Women in Science Roundtable › Welcome and Keynote Lectures › Antonín Holý Memorial Award Lecture › Influenza Symposium › Opening Reception MONDAY, MAY 13, 2019 › Women in Science Award Lecture › Emerging Virus Symposium › Short Presentations 1 › Poster Session 1 › Retrovirus Symposium › ISAR Award of Excellence Presentation › PechaKucha Event with Introduction of First Time Attendees TUESDAY, MAY 14, 2019 › What’s New in Antiviral Research 1 › Short Presentations 2 & 3 › ISAR Award for Outstanding Contributions to the Society Presentation › Career Development Panel › William Prusoff Young Investigator Award Lecture › Medicinal Chemistry Symposium › Poster Session 2 › Networking Reception WEDNESDAY, MAY 15, 2019 › Gertrude Elion Memorial Award Lecture › What’s New in Antiviral Research 2 › Shotgun Oral
    [Show full text]
  • Repurposing Nucleoside Analogs for Human Coronaviruses
    ANTIVIRAL AGENTS crossm Repurposing Nucleoside Analogs for Human Coronaviruses Keivan Zandi,a,b Franck Amblard,a,b Katie Musall,a,b Jessica Downs-Bowen,a,b Ruby Kleinbard,a,b Adrian Oo,a,b Dongdong Cao,c Bo Liang,c Olivia O. Russell,a,b Tamara McBrayer,a,b Leda Bassit,a,b Baek Kim,a,b Raymond F. Schinazia,b aCenter for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA Downloaded from bChildren’s Healthcare of Atlanta, Atlanta, Georgia, USA cDepartment of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA ABSTRACT Coronavirus disease 2019 (COVID-19) is a serious illness caused by se- vere acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or CoV-2). Some reports claimed certain nucleoside analogs to be active against CoV-2 and thus needed con- firmation. Here, we evaluated a panel of compounds and identified novel nucleoside analogs with antiviral activity against CoV-2 and HCoV-OC43 while ruling out others. http://aac.asm.org/ Of significance, sofosbuvir demonstrated no antiviral effect against CoV-2, and its triphosphate did not inhibit CoV-2 RNA polymerase. KEYWORDS SARS-CoV-2, HCoV-OC43, antiviral agents, nucleoside analogs, remdesivir, sofosbuvir, emtricitabine, lamivudine, COVID-19, Coronaviridae oronavirus disease 2019 (COVID-19) has emerged as a global pandemic with Csignificant morbidity and mortality caused by the severe acute respiratory syn- on December 16, 2020 by guest drome coronavirus 2 (SARS-CoV-2 or CoV-2). CoV-2-infected individuals usually develop mild to severe flulike symptoms, whereas other individuals (particularly the elderly harboring underlying chronic health complications, such as diabetes and heart disease, or immunocompromised individuals) are particularly prone to develop severe to fatal clinical outcomes (1, 2).
    [Show full text]
  • Measuring Clinical and Virologic Outcomes in Different Age and Risk Groups
    Measuring Clinical and Virologic Outcomes in Different Age and Risk Groups Prabha Viswanathan, MD Senior Medical Officer Division of Antiviral Products Center for Drug Evaluation and Research, FDA ESCMID eLibrary © by author Overview • Common respiratory viruses and factors impacting the illness they cause • Endpoints in clinical trials – general concepts • Clinical and virologic outcomes in clinical trials of respiratory antivirals • Case Examples in antiviral drug development – Influenza – RSV ESCMID eLibrary 2 © by author Adenovirus (ADV) Coronavirus (CoV) Common Enterovirus (EV) Respiratory Human Metapneumovirus (hMPV) Viruses Influenza Parainfluenza (PIV) Respiratory Syncytial Virus (RSV) Rhinovirus (HRV) ESCMID eLibrary 3 © by author Virus + Host Factors = Clinical Disease ESCMID eLibrary 4 4 © by author Anatomy Environment Health Status Comorbidity Immune Function ESCMID eLibrary 5 5 © by author Impact of Host Factors • The same virus causes a different clinical illness in various population subgroups • The virus causes a similar disease across groups, but host factors affect the severity of the clinical illness ESCMID eLibrary 6 © by author Examples: Virus Causes Different Disease Manifestation RSV Bronchiolitis URI LRTI PIV Croup URI ESCMIDURI = Upper Respiratory Infection; LRTI = LowereLibrary Respiratory Tract Infection 7 © by author Example: Virus Causes Similar Disease Influenza Common signs and symptoms: fever, headache, myalgia, malaise, URI symptoms, cough Populations at risk for more severe disease – respiratory failure ESCMID eLibrary 8 © by author Relevance to Clinical Trials • Understanding when diseases are similar and different is important when designing trials for new antivirals, particularly for endpoint selection • Different endpoints may be needed for trials evaluating the same drug and same virus in different populations (e.g. RSV) • Similar endpoints could be utilized for different drugs and viruses that cause similar clinical illness (e.g.
    [Show full text]
  • Respiratory Syncytial Virus
    RSV Respiratory syncytial virus RSV (Respiratory syncytial virus) is a leading cause of acute respiratory infections. RSV can exploit host immunity and cause a strong inflammatory response that leads to lung damage and virus dissemination. There is a single RSV serotype with two major antigenic subgroups, A and B. RSV is a non-segmented negative-sense single-stranded enveloped RNA virus that belongs to the family of Paramyxoviridae, genus Pneumovirus, subfamily Pneumovirinae. Its 10 genes encode 11 proteins since two overlapping open reading frames in the M2 mRNA yield two distinct matrix proteins, M2-1 and M2-2. The viral envelope contains three proteins, the G glycoprotein, the fusion (F) glycoprotein, and the small hydrophobic (SH) protein. The RSV virus comprises five other structural proteins, the large (L) protein, nucleocapsid (N), phosphoprotein (P), matrix (M), and M2-1, and two non-structural proteins (NS1 and NS2). www.MedChemExpress.com 1 RSV Inhibitors Ac-CoA Synthase Inhibitor1 ALS-8112 Cat. No.: HY-104032 Cat. No.: HY-12983 Ac-CoA Synthase Inhibitor1 is a potent, reversible ALS-8112 is a potent and selective respiratory acetate-dependent acetyl-CoA synthetase 2 syncytial virus (RSV) polymerase inhibitor. The (ACSS2) inhibitor with an IC50 of 0.6 µM. Ac-CoA 5'-triphosphate form of ALS-8112 inhibits RSV Synthase Inhibitor1 inhibits the respiratory polymerase with an IC50 of 0.02 μM. syncytial virus (RSV). Purity: 99.23% Purity: 99.97% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10 mM × 1 mL, 5 mg, 10 mg, 25 mg, 50 mg Size: 10 mM × 1 mL, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg Amentoflavone ent-11β-Hydroxyatis-16-ene-3,14-dione (Didemethyl-ginkgetin) Cat.
    [Show full text]