DOCSLIB.ORG

Ebola Virus Infection: Overview and Update on Prevention and Treatment

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Ebola Virus Infection: Overview and Update on Prevention and Treatment Wayne State University Eugene Applebaum College of Pharmacy and Department of Pharmacy Practice Health Sciences 9-12-2015 Ebola Virus Infection: Overview and Update on Prevention and Treatment Miguel J. Martínez Universitat de Barcelona Abdulbaset M. Salim Wayne State University Juan C. Hurtado Universitat de Barcelona Paul E. Kilgore Wayne State University, [email protected] Follow this and additional works at: https://digitalcommons.wayne.edu/pharm_practice Part of the Epidemiology Commons, International Public Health Commons, and the Pharmacy and Pharmaceutical Sciences Commons Recommended Citation Martínez, M.J., Salim, A.M., Hurtado, J.C. et al. Ebola Virus Infection: Overview and Update on Prevention and Treatment. Infect Dis Ther 4, 365–390 (2015). https://doi.org/10.1007/s40121-015-0079-5 This Article is brought to you for free and open access by the Eugene Applebaum College of Pharmacy and Health Sciences at DigitalCommons@WayneState. It has been accepted for inclusion in Department of Pharmacy Practice by an authorized administrator of DigitalCommons@WayneState. Infect Dis Ther (2015) 4:365–390 DOI 10.1007/s40121-015-0079-5 REVIEW Ebola Virus Infection: Overview and Update on Prevention and Treatment Miguel J. Martı´nez • Abdulbaset M. Salim • Juan C. Hurtado • Paul E. Kilgore To view enhanced content go to www.infectiousdiseases-open.com Received: July 30, 2015 / Published online: September 12, 2015 Ó The Author(s) 2015. This article is published with open access at Springerlink.com ABSTRACT Complete and using the search terms Ebola, Ebola virus disease, Ebola hemorrhagic fever, In 2014 and 2015, the largest Ebola virus West Africa outbreak, Ebola transmission, disease (EVD) outbreak in history affected Ebola symptoms and signs, Ebola diagnosis, large populations across West Africa. The Ebola treatment, vaccines for Ebola and goal of this report is to provide an update clinical trials on Ebola. Through 22 July on the epidemic and review current progress 2015, a total of 27,741 EVD cases and 11,284 in the development, evaluation and deaths were reported from all affected deployment of prevention and treatment countries. Several therapeutic agents and strategies for EVD. Relevant information was novel vaccines for EVD have been developed identified through a comprehensive literature and are now undergoing evaluation. search using Medline, PubMed and CINAHL Concurrent with active case investigation, contact tracing, surveillance and supportive Electronic supplementary material The online version of this article (doi:10.1007/s40121-015-0079-5) care to patients and communities, there has contains supplementary material, which is available to been rapid progress in the development of authorized users. new therapies and vaccines against EVD. M. J. Martı´nez Á J. C. Hurtado Continued focus on strengthening clinical Department of Clinical Microbiology, Hospital and public health infrastructure will have Clinic, Universitat de Barcelona, Barcelona, Spain direct benefits in controlling the spread of M. J. Martı´nez EVD and will provide a strong foundation for ISGlobal Barcelona Institute for Global Health, Barcelona, Spain deployment of new drugs and vaccines to affected countries when they become A. M. Salim Á P. E. Kilgore (&) Department of Pharmacy Practice, Eugene available. The unprecedented West Africa Applebaum College of Pharmacy and Health Ebola outbreak, response measures, and Sciences, Wayne State University, Detroit, MI, USA e-mail: [email protected] ensuing drug and vaccine development suggest that new tools for Ebola control may P. E. Kilgore Department of Family Medicine and Public Health be available in the near future. Sciences, Wayne State University, Detroit, MI, USA 366 Infect Dis Ther (2015) 4:365–390 Keywords: Africa; Anti-viral; EBOV; EVD; EVD. We reviewed reports from Hemorrhagic fever; Immunization; Treatment; peer-reviewed literature published from 1993 Vaccine through 2015 and cited in several electronic databases including Medline, PubMed and CINAHL Complete on ‘‘Ebola,’’ ‘‘Ebola virus INTRODUCTION disease,’’ ‘‘Ebola hemorrhagic fever,’’ ‘‘West Africa outbreak,’’ ‘‘Ebola transmission,’’ ‘‘Ebola Ebola virus (EBOV) derived its name from the symptoms and signs,’’ ‘‘Ebola diagnosis,’’ Ebola River in Democratic Republic of Congo ‘‘Ebola treatment,’’ ‘‘vaccines for Ebola’’ and (DRC) (formerly Zaire) where the first Ebola ‘‘clinical trials on Ebola’’ (Fig. 1). The gray virus disease (EVD) outbreak was identified in literature, health organization websites, 1976 [1]. Historically, outbreaks of EVD have clinical trial registries and corporate websites been confined to a single country and have were inspected and reviewed to identify been brought under control by domestic health up-to-date information relevant to Ebola. agencies working in conjunction with Studies were included in the proposed international organizations such as the World literature review if they (1) were published Health Organization (WHO). However, since in the English language; (2) were full-text March 2014, West African countries, notably articles; (3) focused on Ebola virus virology, Guinea, Liberia and Sierra Leon, have epidemiology, diagnosis, treatment and experienced the largest EVD outbreak in their clinical trials on vaccines and treatment; (4) history [2]. Although the origins of EVD in the were published between 1993 and 2015; (5) most recent outbreak remain under were published in peer-reviewed journals. We investigation, the spread of EBOV occurred excluded studies if they (1) were not full-text rapidly because of a number of factors articles; (2) were published before 1993; (3) including funeral and burial practices for were published in non-peer-reviewed decedents [3, 4]. journals. We identified 156 studies for The scope and severity of the EVD outbreak inclusion in this review. Seventy-one studies underscore the urgent need for development focused on epidemiology, public health and evaluation of affordable therapeutic and issues, clinical syndrome of EVD and prophylactic agents that can be made available diagnostic tools. An additional 89 studies for at-risk populations across Africa. Over the provided information on therapeutic and past 17 months, the West Africa EVD outbreak vaccine clinical trials that target EBOV. Data has provided an important opportunity to were abstracted from published and consider use of and evaluate several unpublished reports to describe disease therapeutic and prophylactic agents (e.g., patterns, burden of illness in past and vaccines) to determine their safety and efficacy presentoutbreaksaswellaseffectsof [5, 6]. investigational therapies and vaccines. This Review Methods article is based on previously conducted studies and does not involve any new For this review, we considered published and studies of human or animal subjects unpublished reports related to EBOV and performed by any of the authors. Infect Dis Ther (2015) 4:365–390 367 Fig. 1 Flowchart for the literature search Virology and Bundibugyo ebolavirus). In contrast, the genus Marburgvirus contains a single virus Filoviruses (family Filoviridae) are enveloped, species (Marburg marburgvirus), and two linear, non-segmented, negative and distinct viruses have been recognized, single-stranded RNA viruses belonging to the Marburg virus and Ravn virus [9–11]. In 2011, order Mononegavirales. Ebolavirus and a novel third genus of filovirus named Marburgvirus are the two genera of filoviruses Cuevavirus was reported from post-mortem that have been identified to cause severe tissues of bats collected in 2002 in Northern disease in humans [7, 8]. Within the genus Spain [12]. Cuevavirus has not been grown in Ebolavirus, five viruses are recognized (EBOV, cell culture, and its pathogenic potential for Sudan virus, Reston virus, Taı¨ Forest virus and humans remains unknown. To date, a single Bundibugyo virus) with each representing a species (Lloviu cuevavirus) has been approved by different virus species (Zaire ebolavirus, Sudan the International Committee on Taxonomy of ebolavirus, Reston ebolavirus, Taı¨ Forest ebolavirus Viruses (ICTV) [9]. 368 Infect Dis Ther (2015) 4:365–390 The current West Africa outbreak is caused remained stable during the current Ebola by Zaire ebolavirus, which shows 97% identity to outbreak [23]. EBOV strains from the DRC and Gabon [13]. The genome of EBOV contains seven genes Epidemiology and Outbreaks named nucleoprotein (NP), virion protein (VP) 24, VP30, VP35, VP40, glycoprotein (GP) and L Ebola viruses have been responsible for 33 protein [14]. Each one of these genes encodes a outbreaks in six African countries [2]. corresponding structural protein. The main Historically, the outbreaks have affected proteins targeted by experimental treatments hundreds of individuals where effective are the NP, VP35, GP, VP24 and L protein. NP is control of outbreaks was achieved primarily the main component of the viral nucleocapsid through isolation of cases and contact tracing. and encapsulates the viral RNA. VP35 is also However, from 2000, EVD outbreaks have been part of the nucleocapsid and, together with recognized almost every year with substantial VP24, interferes with innate host immunity. variation in morbidity and case-fatality rates The surface GP is responsible for the attachment ranging from 24% to 81% [24]. High to the cellular receptor and viral entry. L protein case-fatality rates have been associated with is the RNA-dependent RNA polymerase [15–20]. the Zaire and Sudan subtypes [25]. In the Early reports
Load more

Recommended publications
  • A Multicenter, Multi-Outbreak, Randomized, Controlled Safety And
    2018 Ebola MCM RCT Protocol Page 1 of 92 IND#: 125530 CONFIDENTIAL 4 October 2019, version 7.0 A Multicenter, Multi-Outbreak, Randomized, Controlled Safety and Efficacy Study of Investigational Therapeutics for the Treatment of Patients with Ebola Virus Disease Short Title: 2018 Ebola MCM RCT Protocol Sponsored by: Office of Clinical Research Policy and Regulatory Operations (OCRPRO) National Institute of Allergy and Infectious Diseases 5601 Fishers Lane Bethesda, MD 20892 NIH Protocol Number: 19-I-0003 Protocol IND #: 125530 ClinicalTrials.gov Number: NCT03719586 Date: 4 October 2019 Version: 7.0 CONFIDENTIAL This document is confidential. No part of it may be transmitted, reproduced, published, or used by other persons without prior written authorization from the study sponsor and principal investigator. 2018 Ebola MCM RCT Protocol Page 2 of 92 IND#: 125530 CONFIDENTIAL 4 October 2019, version 7.0 KEY ROLES DRC Principal Investigator: Jean-Jacques Muyembe-Tamfum, MD, PhD Director-General, DRC National Institute for Biomedical Research Professor of Microbiology, Kinshasa University Medical School Kinshasa Gombe Democratic Republic of the Congo Phone: +243 898949289 Email: [email protected] Other International Investigators: see Appendix E Statistical Lead: Lori Dodd, PhD Biostatistics Research Branch, DCR, NIAID 5601 Fishers Lane, Room 4C31 Rockville, MD 20852 Phone: 240-669-5247 Email: [email protected] U.S. Principal Investigator: Richard T. Davey, Jr., MD Clinical Research Section, LIR, NIAID, NIH Building 10, Room 4-1479, Bethesda,
    [Show full text]
  • COVID-19) Pandemic on National Antimicrobial Consumption in Jordan
    antibiotics Article An Assessment of the Impact of Coronavirus Disease (COVID-19) Pandemic on National Antimicrobial Consumption in Jordan Sayer Al-Azzam 1, Nizar Mahmoud Mhaidat 1, Hayaa A. Banat 2, Mohammad Alfaour 2, Dana Samih Ahmad 2, Arno Muller 3, Adi Al-Nuseirat 4 , Elizabeth A. Lattyak 5, Barbara R. Conway 6,7 and Mamoon A. Aldeyab 6,* 1 Clinical Pharmacy Department, Jordan University of Science and Technology, Irbid 22110, Jordan; [email protected] (S.A.-A.); [email protected] (N.M.M.) 2 Jordan Food and Drug Administration (JFDA), Amman 11181, Jordan; [email protected] (H.A.B.); [email protected] (M.A.); [email protected] (D.S.A.) 3 Antimicrobial Resistance Division, World Health Organization, Avenue Appia 20, 1211 Geneva, Switzerland; [email protected] 4 World Health Organization Regional Office for the Eastern Mediterranean, Cairo 11371, Egypt; [email protected] 5 Scientific Computing Associates Corp., River Forest, IL 60305, USA; [email protected] 6 Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK; [email protected] 7 Institute of Skin Integrity and Infection Prevention, University of Huddersfield, Huddersfield HD1 3DH, UK * Correspondence: [email protected] Citation: Al-Azzam, S.; Mhaidat, N.M.; Banat, H.A.; Alfaour, M.; Abstract: Coronavirus disease 2019 (COVID-19) has overlapping clinical characteristics with bacterial Ahmad, D.S.; Muller, A.; Al-Nuseirat, respiratory tract infection, leading to the prescription of potentially unnecessary antibiotics. This A.; Lattyak, E.A.; Conway, B.R.; study aimed at measuring changes and patterns of national antimicrobial use for one year preceding Aldeyab, M.A.
    [Show full text]
  • Plotting the Course of Ebola Vaccines
    March 2016 Ebola Vaccine Team B Plotting the Course of Ebola Vaccines CHALLENGES AND UNANSWERED QUESTIONS Plotting the Course of Ebola Vaccines CHALLENGES AND UNANSWERED QUESTIONS March 2016 Plotting the Course of Ebola Vaccines: Challenges and Unanswered Questions was made possible through a joint project of Wellcome Trust and the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota. Wellcome Trust is a global charitable foundation dedicated to improving health by supporting bright minds in science, the humanities and social sciences, and public engagement. Wellcome Trust is independent of both political and commercial interests. For more information, visit www.wellcome.ac.uk/index.htm. The Center for Infectious Disease Research and Policy (CIDRAP), founded in 2001, is a global leader in addressing public health preparedness and emerging infectious disease response. Part of the Academic Health Center at the University of Minnesota, CIDRAP works to prevent illness and death from targeted infectious disease threats through research and the translation of scientific information into real-world, practical applications, policies, and solutions. For more information, visit www.cidrap.umn.edu. Permissions: CIDRAP authorizes the making and distribution of copies or excerpts (in a manner that does not distort the meaning of the original) of this information for non-commercial, educational purposes within organizations. The following credit line must appear: “Reprinted with permission of the Center for Infectious Disease Research and Policy. Copyright Regents of the University of Minnesota.” This publication is designed to provide accurate and authoritative information with regard to the subject matter covered. It is published with the understanding that the publisher is not engaged in rendering legal, medical, or other professional services.
    [Show full text]
  • Brincidofovir Is Highly Efficacious in Controlling Adenoviremia In
    Brincidofovir is highly efficacious in controlling adenoviremia in pediatric recipients of hematopoietic cell transplant Prashant Hiwarkar,1 Persis Amrolia,2 Ponni Sivaprakasam,3 Su Han Lum,4 Hemalatha Doss,5 Ciara O’Rafferty,1 Toni Petterson,6 Katharine Patrick,7 Juliana Silva,2 Mary Slatter,5 Sarah Lawson,1 Kanchan Rao,2 Colin Steward,3 Adam Gassas,3 Paul Veys,2 Robert Wynn4 On behalf of the UK Paediatric BMT Group 1Department of Haematology and Bone Marrow Transplantation, Birmingham Children’s Hospital, Birmingham, UK; 2Department of Bone Marrow Transplantation, Great Ormond Street Hospital for Children, London; 3Department of Bone Marrow Transplantation, Royal Hospital for Children, Bristol, UK; 4Department of Bone Marrow Transplantation, Royal Manchester Children's Hospital, Manchester, UK; 5Department of Bone Marrow Transplantation, Great North Children's Hospital, Newcastle upon Tyne, UK; 6Department of Bone Marrow Transplantation, Royal Marsden Hospital, Sutton, UK; 7Department of Bone Marrow Transplantation, Sheffield Children's Hospital, Sheffield, UK Address for Correspondence: [email protected] Department of Haematology and Bone Marrow transplantation Birmingham Children’s Hospital, Steelhouse Lane, Birmingham, UK B4 6NH Tel. +44 (0)121 333 9999 Key points Brincidofovir has superior anti-adenoviral activity and safety profile compared to Cidofovir. Brincidofovir is highly efficacious in controlling adenoviraemia during lymphopenic phase of HCT. Summary Cidofovir is pre-emptively used for controlling adenoviremia and preventing disseminated viral disease in hematopoietic cell transplant (HCT) recipients but does not lead to resolution of viremia without T-cell immune-reconstitution. The lipid conjugated prodrug of Cidofovir, Brincidofovir, has improved oral bioavailability and achieves higher intracellular concentrations of active drug.
    [Show full text]
  • Ebola Hemorrhagic Fever: Properties of the Pathogen and Development of Vaccines and Chemotherapeutic Agents O
    ISSN 00268933, Molecular Biology, 2015, Vol. 49, No. 4, pp. 480–493. © Pleiades Publishing, Inc., 2015. Original Russian Text © O.I. Kiselev, A.V. Vasin, M.P. Shevyryova, E.G. Deeva, K.V. Sivak, V.V. Egorov, V.B. Tsvetkov, A.Yu. Egorov, E.A. RomanovskayaRomanko, L.A. Stepanova, A.B. Komissarov, L.M. Tsybalova, G.M. Ignatjev, 2015, published in Molekulyarnaya Biologiya, 2015, Vol. 49, No. 4, pp. 541–554. REVIEWS UDC 578.2,578.76 Ebola Hemorrhagic Fever: Properties of the Pathogen and Development of Vaccines and Chemotherapeutic Agents O. I. Kiseleva, A. V. Vasina, b, M. P. Shevyryovac, E. G. Deevaa, K. V. Sivaka, V. V. Egorova, V. B. Tsvetkova, d, A. Yu. Egorova, E. A. RomanovskayaRomankoa, L. A. Stepanovaa, A. B. Komissarova, L. M. Tsybalovaa, and G. M. Ignatjeva a Institute of Influenza, Ministry of Health of the Russian Federation, St. Petersburg, 197376 Russia; email: [email protected] b St. Petersburg State Polytechnic University, St. Petersburg, 195251 Russia c Ministry of Health of the Russian Federation, Moscow, 127994 Russia d Topchiev Institute of Petrochemical Synthesis, Moscow, 119991 Russia Received December 29, 2014; in final form, January 16, 2015 Abstract—Ebola hemorrhagic fever (EHF) epidemic currently ongoing in West Africa is not the first among numerous epidemics in the continent. Yet it seems to be the worst EHF epidemic outbreak caused by Ebola virus Zaire since 1976 as regards its extremely large scale and rapid spread in the population. Experiments to study the agent have continued for more than 20 years. The EHF virus has a relatively simple genome with seven genes and additional reading frame resulting from RNA editing.
    [Show full text]
  • Kinase Inhibitors and Nucleoside Analogues As Novel Therapies to Inhibit HIV-1 Or ZEBOV Replication
    Kinase Inhibitors and Nucleoside Analogues as Novel Therapies to Inhibit HIV-1 or ZEBOV Replication by Stephen D. S. McCarthy A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Laboratory Medicine and Pathobiology University of Toronto © Copyright by Stephen D. S. McCarthy (2017) Kinase Inhibitors and Nucleoside Analogues as Novel Therapies to Inhibit HIV-1 or ZEBOV Replication Stephen D.S. McCarthy Doctor of Philosophy Graduate Department of Laboratory Medicine and Pathobiology University of Toronto 2017 Abstract Without a vaccine for Human Immunodeficiency Virus type 1 (HIV-1), or approved therapy for treating Zaire Ebolavirus (ZEBOV) infection, new means to treat either virus during acute infection are under intense investigation. Repurposing tyrosine kinase inhibitors of known specificity may not only inhibit HIV-1 replication, but also treat associated inflammation or neurocognitive disorders caused by chronic HIV-1 infection. Moreover, tyrosine kinase inhibitors may effectively treat other infections, including ZEBOV. In addition, established nucleoside/nucleotide analogues that effectively inhibit HIV-1 infection, could also be repurposed to inhibit ZEBOV replication. In this work the role of two host cell kinases, cellular protoncogene SRC (c-SRC) and Protein Tyrosine Kinase 2 Beta (PTK2B), were found to have key roles during early HIV-1 replication in primary activated CD4+ T-cells ex vivo. siRNA knockdown of either kinase increased intracellular reverse transcripts and decreased nuclear proviral integration, suggesting they act at the level of pre-integration complex (PIC) formation or PIC nuclear translocation. c-SRC siRNA knockdown consistently reduced p24 levels of IIIB(X4) and Ba-L(R5) infection, or luciferase ii activity of HXB2(X4) or JR-FL(R5) recombinant viruses, prompting further drug inhibition studies of this kinase.
    [Show full text]
  • Leafbio Announces Conclusion of Zmapp™ Clinical Trial Therapy to Treat Ebola Shows Promise
    FOR IMMEDIATE RELEASE Contact: Kerri Lyon [email protected] February 23, 2016 917-348-2191 LeafBio Announces Conclusion of ZMapp™ Clinical Trial Therapy to Treat Ebola Shows Promise February 23, 2016 – SAN DIEGO – LeafBio, Inc., the commercial arm of Mapp Biopharmaceutical, Inc., announced today results from the Prevail II clinical trial of its ZMapp™ therapy for treatment of Ebola Virus Disease. The trial, conducted in Liberia, Sierra Leone, Guinea and the United States over the course of nearly a year, was initiated to evaluate the efficacy of ZMapp™ in treating Ebola Virus Disease and concluded on January 29, 2016. While the trial did not ultimately enroll enough patients to produce definitive results, researchers said the drug was well-tolerated and showed promise. As a result, the U.S. Food and Drug Administration has encouraged Mapp Biopharmaceutical to continue to make ZMapp™ available to patients under an expanded access treatment protocol during the product’s ongoing development. “We are encouraged by these results,” said Dr. Larry Zeitlin, president of Mapp Bio. “The outcome of this truncated study is supportive of ZMapp’s™ antiviral activity in humans. While this trial is not definitive, its results are consistent with the favorable results observed in animal efficacy testing in nonhuman primates.” The study closed short of its enrollment goals due to the waning of the Ebola epidemic in West Africa. Liberia, Sierra Leone and Guinea, the three countries hardest hit by the epidemic, had been declared Ebola-free by the World Health Organization at various points through the end of 2015, and there are presently no confirmed cases in the region.
    [Show full text]
  • Situación Actual Del Tratamiento Farmacológico Frente a La Enfermedad Causada Por El Virus Ébola
    Revisión Jordi Reina Situación actual del tratamiento farmacológico frente a la enfermedad causada por el virus Ébola Unidad de Virología. Servicio de Microbiología. Hospital Universitario Son Espases. Palma de Mallorca RESUMEN Current status of drug treatment against the disease caused by the Ebola virus La reciente epidemia de enfermedad causada por el virus Ébola ha puesto en evidencia la necesidad de desarrollar y dis- ABSTRACT poner de fármacos específicos para hacer frente a esta entidad. De acuerdo con los datos virológicos se han diseñado algunos The recent epidemic of disease caused by the Ebola virus fármacos nuevos y se ha comprobado que otros podrían tener has highlighted the need to develop specific drugs and have to eficacia frente a este virus. deal with this entity. According to virological analysis they have Las principales líneas terapéuticas se basan en la inmu- been designed to give you some new drugs and are proven to noterapia (suero de pacientes convalescientes y anticuerpos others might be effective against this virus. monoclonales específicos), en fármacos antivirales (favipiora- The main lines of therapy are based on immunotherapy vir, BCX4430, Brincidofovir), RNAs de interferencia (TKM-Ébola) (convalescent serum of patients and specific monoclonal an- y oligonucleótidos sin sentido (morfolino fosforodiamidato) y tibodies), antiviral drugs (favipiravir, BCX4430, brincidofovir), otros fármacos no antivirales (clomifeno, NSC62914, FGI-103, interfering RNAs (TKM-Ebola) and antisense oligonucleotides amilorida y la ouabaina). (morpholino phosphorodiamidate) and other drugs no antiviral Los estudios existentes son escasos y principalmente en (clomiphene NSC62914, FGI-103, amiloride and ouabain). modelos animales y los ensayos clínicos han quedado la ma- Existing studies are scarce and mainly in animal models yoría inconclusos por la disminución drástica del número de and clinical trials have been inconclusive most by the drastic nuevos casos.
    [Show full text]
  • The Role of Brincidofovir in Preparation for a Potential Smallpox Outbreak
    viruses Perspective The Role of Brincidofovir in Preparation for a Potential Smallpox Outbreak Scott A. Foster 1,*, Scott Parker 2 ID and Randall Lanier 1 1 Chimerix, Durham, NC 27713, USA; [email protected] 2 Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-919-597-7741 Received: 29 September 2017; Accepted: 26 October 2017; Published: 30 October 2017 Abstract: Smallpox (variola) virus is considered a Category A bioterrorism agent due to its ability to spread rapidly and the high morbidity and mortality rates associated with infection. Current recommendations recognize the importance of oral antivirals and call for having at least two smallpox antivirals with different mechanisms of action available in the event of a smallpox outbreak. Multiple antivirals are recommended due in large part to the propensity of viruses to become resistant to antiviral therapy, especially monotherapy. Advances in synthetic biology heighten concerns that a bioterror attack with variola would utilize engineered resistance to antivirals and potentially vaccines. Brincidofovir, an oral antiviral in late stage development, has proven effective against orthopoxviruses in vitro and in vivo, has a different mechanism of action from tecovirimat (the only oral smallpox antiviral currently in the US Strategic National Stockpile), and has a resistance profile that reduces concerns in the scenario of a bioterror attack using genetically engineered smallpox. Given the devastating potential of smallpox as a bioweapon, preparation of a multi-pronged defense that accounts for the most obvious bioengineering possibilities is strategically imperative. Keywords: smallpox; variola virus; bioterrorism; bioweapon; brincidofovir; CMX001; antiviral 1.
    [Show full text]
  • Determining Ribavirin's Mechanism of Action Against Lassa Virus Infection
    www.nature.com/scientificreports OPEN Determining Ribavirin’s mechanism of action against Lassa virus infection Received: 28 March 2017 Paola Carrillo-Bustamante1, Thi Huyen Tram Nguyen2,3, Lisa Oestereich4,5, Stephan Accepted: 4 August 2017 Günther4,5, Jeremie Guedj 2,3 & Frederik Graw1 Published: xx xx xxxx Ribavirin is a broad spectrum antiviral which inhibits Lassa virus (LASV) replication in vitro but exhibits a minor effect on viremiain vivo. However, ribavirin significantly improves the disease outcome when administered in combination with sub-optimal doses of favipiravir, a strong antiviral drug. The mechanisms explaining these conflicting findings have not been determined, so far. Here, we used an interdisciplinary approach combining mathematical models and experimental data in LASV-infected mice that were treated with ribavirin alone or in combination with the drug favipiravir to explore different putative mechanisms of action for ribavirin. We test four different hypotheses that have been previously suggested for ribavirin’s mode of action: (i) acting as a mutagen, thereby limiting the infectivity of new virions; (ii) reducing viremia by impairing viral production; (iii) modulating cell damage, i.e., by reducing inflammation, and (iv) enhancing antiviral immunity. Our analysis indicates that enhancement of antiviral immunity, as well as effects on viral production or transmission are unlikely to be ribavirin’s main mechanism mediating its antiviral effectiveness against LASV infection. Instead, the modeled viral kinetics suggest that the main mode of action of ribavirin is to protect infected cells from dying, possibly reducing the inflammatory response. Lassa fever (LF) is a severe and often fatal hemorrhagic disease caused by Lassa virus (LASV), a member of the Arenaviridae virus family.
    [Show full text]
  • Integrated Computational Approach for Virtual Hit Identification Against
    International Journal of Molecular Sciences Article Integrated Computational Approach for Virtual Hit Identification against Ebola Viral Proteins VP35 and VP40 Muhammad Usman Mirza 1,2,*,† and Nazia Ikram 2 1 Centre for Research in Molecular Medicine (CRiMM), The University of Lahore, Defense Road, Lahore 54000, Pakistan 2 Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore 54000, Pakistan; [email protected] * Correspondence: [email protected] or [email protected]; Tel.: +92-333-839-6037 † Current address: Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, Medicinal Chemistry, University of Leuven, Leuven B-3000, Belgium. Academic Editors: Christo Z. Christov and Tatyana Karabencheva-Christova Received: 28 July 2016; Accepted: 22 September 2016; Published: 26 October 2016 Abstract: The Ebola virus (EBOV) has been recognised for nearly 40 years, with the most recent EBOV outbreak being in West Africa, where it created a humanitarian crisis. Mortalities reported up to 30 March 2016 totalled 11,307. However, up until now, EBOV drugs have been far from achieving regulatory (FDA) approval. It is therefore essential to identify parent compounds that have the potential to be developed into effective drugs. Studies on Ebola viral proteins have shown that some can elicit an immunological response in mice, and these are now considered essential components of a vaccine designed to protect against Ebola haemorrhagic fever. The current study focuses on chemoinformatic approaches to identify virtual hits against Ebola viral proteins (VP35 and VP40), including protein binding site prediction, drug-likeness, pharmacokinetic and pharmacodynamic properties, metabolic site prediction, and molecular docking. Retrospective validation was performed using a database of non-active compounds, and early enrichment of EBOV actives at different false positive rates was calculated.
    [Show full text]
  • A Library of Nucleotide Analogues Terminate RNA Synthesis Catalyzed by Polymerases of Coronaviruses Causing SARS and COVID-19
    bioRxiv preprint doi: https://doi.org/10.1101/2020.04.23.058776; this version posted April 25, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. A Library of Nucleotide Analogues Terminate RNA Synthesis Catalyzed by Polymerases of Coronaviruses Causing SARS and COVID-19 Steffen Jockusch1,2,#, Chuanjuan Tao1,3,#, Xiaoxu Li1,3,#, Thomas K. Anderson5,6, Minchen Chien1,3, Shiv Kumar1,3, James J. Russo1,3, Robert N. Kirchdoerfer5,6,*, Jingyue Ju1,3,4,* 1Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027; Departments of 2 Chemistry, 3Chemical Engineering, and 4Pharmacology, Columbia University, New York, NY 10027; 5Departments of Biochemistry and 6Institute of Molecular Virology, University of Wisconsin-Madison, Madison, WI 53706 #SJ, CT and XL contributed equally to this work. *To whom correspondence should be addressed: [email protected] (JJ); [email protected] (RNK) Abstract SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 worldwide pandemic. We previously demonstrated that five nucleotide analogues inhibit the SARS-CoV-2 RNA- dependent RNA polymerase (RdRp), including the active triphosphate forms of Sofosbuvir, Alovudine, Zidovudine, Tenofovir alafenamide and Emtricitabine. We report here the evaluation of a library of additional nucleoside triphosphate analogues with a variety of structural and chemical features as inhibitors of the RdRps of SARS-CoV and SARS-CoV-2. These features include modifications on the sugar (2’ or 3’ modifications, carbocyclic, acyclic, or dideoxynucleotides) or on the base.
    [Show full text]