The prophylactic and therapeutic efficacy of the broadly active antiviral ribonucleoside N 4 -Hydroxycytidine (EIDD-1931) in a mouse model of lethal Ebola virus infection.

Autor: Bluemling GR; Emory Institute for Drug Development (EIDD), 954 North Gatewood Road NE, Atlanta, GA, 30329, USA; Drug Innovation Ventures at Emory (DRIVE), 1230 Peachtree Street NE, Suite 3875, Atlanta, GA, 30309, USA., Mao S; Emory Institute for Drug Development (EIDD), 954 North Gatewood Road NE, Atlanta, GA, 30329, USA., Natchus MG; Emory Institute for Drug Development (EIDD), 954 North Gatewood Road NE, Atlanta, GA, 30329, USA., Painter W; Ridgeback Biotherapeutics, LP, 3480 Main Highway, Unit 402, Miami, FL, 33133, USA., Mulangu S; Ridgeback Biotherapeutics, LP, 3480 Main Highway, Unit 402, Miami, FL, 33133, USA., Lockwood M; Emory Institute for Drug Development (EIDD), 954 North Gatewood Road NE, Atlanta, GA, 30329, USA., De La Rosa A; Emory Institute for Drug Development (EIDD), 954 North Gatewood Road NE, Atlanta, GA, 30329, USA; Drug Innovation Ventures at Emory (DRIVE), 1230 Peachtree Street NE, Suite 3875, Atlanta, GA, 30309, USA., Brasel T; Department of Microbiology & Immunology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555, USA; Office of Regulated Nonclinical Studies, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX, 77555, USA; The Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX, 77555, USA; Sealy Institute for Vaccine Sciences, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX, 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX, 77555, USA., Comer JE; Department of Microbiology & Immunology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555, USA; Office of Regulated Nonclinical Studies, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX, 77555, USA; The Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX, 77555, USA; Sealy Institute for Vaccine Sciences, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX, 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX, 77555, USA; Institute of Translational Sciences, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX, 77555, USA., Freiberg AN; Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0609, USA; The Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX, 77555, USA; Sealy Institute for Vaccine Sciences, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX, 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX, 77555, USA., Kolykhalov AA; Emory Institute for Drug Development (EIDD), 954 North Gatewood Road NE, Atlanta, GA, 30329, USA; Drug Innovation Ventures at Emory (DRIVE), 1230 Peachtree Street NE, Suite 3875, Atlanta, GA, 30309, USA. Electronic address: a.kolykhalov@emory.edu., Painter GR; Emory Institute for Drug Development (EIDD), 954 North Gatewood Road NE, Atlanta, GA, 30329, USA; Drug Innovation Ventures at Emory (DRIVE), 1230 Peachtree Street NE, Suite 3875, Atlanta, GA, 30309, USA; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Road, 5001 Rollins Research Center, Atlanta, GA, 30322, USA.
Jazyk: angličtina
Zdroj: Antiviral research [Antiviral Res] 2023 Jan; Vol. 209, pp. 105453. Date of Electronic Publication: 2022 Nov 13.
DOI: 10.1016/j.antiviral.2022.105453
Abstrakt: The unprecedented magnitude of the 2013-2016 Ebola virus (EBOV) epidemic in West Africa resulted in over 11 000 deaths and spurred an international public health emergency. A second outbreak in 2018-2020 in DRC resulted in an additional >3400 cases and nearly 2300 deaths (WHO, 2020). These large outbreaks across geographically diverse regions highlight the need for the development of effective oral therapeutic agents that can be easily distributed for self-administration to populations with active disease or at risk of infection. Herein, we report the in vivo efficacy of N 4 -hydroxycytidine (EIDD-1931), a broadly active ribonucleoside analog and the active metabolite of the prodrug EIDD-2801 (molnupiravir), in murine models of lethal EBOV infection. Twice daily oral dosing with EIDD-1931 at 200 mg/kg for 7 days, initiated either with a prophylactic dose 2 h before infection, or as therapeutic treatment starting 6 h post-infection, resulted in 92-100% survival of mice challenged with lethal doses of EBOV, reduced clinical signs of Ebola virus disease (EVD), reduced serum virus titers, and facilitated weight loss recovery. These results support further investigation of molnupiravir as a potential therapeutic or prophylactic treatment for EVD.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GRB, MGN, AAK and GRP receive licensing fees and royalties based on Emory’s sublicense of the molnupiravir technology to Ridgeback Biotherapeutics, and a family member of GRP serves as the Chief Medical Officer of Ridgeback. A family member of WP receives licensing fees and royalties based on Emory’s sublicense of the molnupiravir technology to Ridgeback Biotherapeutics. This technology is the subject of the research described in this paper. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. SMulangu is listed as inventor on the patent application for mAb 114 (Ebanga™ (ansuvimab-zykl); WP and SMulangu are employees at Ridgeback Biotherapeutics. SMao, ML, ADLR, TB, JEC, ANF have no conflicts to declare.
(Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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