Communication DOI: 10.5582/Ddt.2020.01012
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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. -
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. -
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. -
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 -
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. -
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 . -
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 -
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. -
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. -
Critical Care Management of Adults with Community-Acquired Severe
Intensive Care Med https://doi.org/10.1007/s00134-020-05943-5 NARRATIVE REVIEW Critical care management of adults with community-acquired severe respiratory viral infection Yaseen M. Arabi1,2,3* , Robert Fowler4,5,6 and Frederick G. Hayden7 © 2020 Springer-Verlag GmbH Germany, part of Springer Nature Abstract With the expanding use of molecular assays, viral pathogens are increasingly recognized among critically ill adult patients with community-acquired severe respiratory illness; studies have detected respiratory viral infections (RVIs) in 17–53% of such patients. In addition, novel pathogens including zoonotic coronaviruses like the agents causing Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS) and the 2019 novel coronavirus (2019 nCoV) are still being identifed. Patients with severe RVIs requiring ICU care present typically with hypoxemic respiratory failure. Oseltamivir is the most widely used neuraminidase inhibitor for treatment of infuenza; data sug- gest that early use is associated with reduced mortality in critically ill patients with infuenza. At present, there are no antiviral therapies of proven efcacy for other severe RVIs. Several adjunctive pharmacologic interventions have been studied for their immunomodulatory efects, including macrolides, corticosteroids, cyclooxygenase-2 inhibitors, sirolimus, statins, anti-infuenza immune plasma, and vitamin C, but none is recommended at present in severe RVIs. Evidence-based supportive care is the mainstay for management of severe respiratory viral infection. Non-invasive ventilation in patients with severe RVI causing acute hypoxemic respiratory failure and pneumonia is associated with a high likelihood of transition to invasive ventilation. Limited existing knowledge highlights the need for data regarding supportive care and adjunctive pharmacologic therapy that is specifc for critically ill patients with severe RVI. -
A Meeting Report from the 6Th Isirv Antiviral Group Conference T
Antiviral Research 167 (2019) 45–67 Contents lists available at ScienceDirect Antiviral Research journal homepage: www.elsevier.com/locate/antiviral Advances in respiratory virus therapeutics – A meeting report from the 6th isirv Antiviral Group conference T ∗ John H. Beigela, , Hannah H. Namb, Peter L. Adamsc, Amy Kraffta, William L. Inced, Samer S. El-Kamaryd, Amy C. Simse a National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA 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 ARTICLE INFO ABSTRACT Keywords: The International Society for Influenza and other Respiratory Virus Diseases held its 6th Antiviral Group (isirv- Influenza AVG) conference in Rockville, Maryland, November 13–15, 2018. The three-day program was focused on Respiratory syncytial virus therapeutics towards seasonal and pandemic influenza, respiratory syncytial virus, coronaviruses including Coronavirus MERS-CoV and SARS-CoV, human rhinovirus, and other respiratory viruses. Updates were presented on several Antiviral therapy influenza antivirals including baloxavir, CC-42344, VIS410, immunoglobulin, immune plasma, MHAA4549A, Host-directed therapeutics 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 in- cluding nitazoxanide, eritoran, and diltiazem. -
Stembook 2018.Pdf
The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.