The prophylactic and therapeutic efficacy of the broadly active antiviral ribonucleoside N4-Hydroxycytidine (EIDD-1931) in a mouse model of lethal Ebola virus infection

Gregory R Bluemling; Shuli Mao; Michael G Natchus; Wendy Painter; Sabue Mulangu; Mark Lockwood; Abel De La Rosa; Trevor Brasel; Jason E Comer; Alexander N Freiberg; Alexander A Kolykhalov; George R Painter

doi:10.1016/j.antiviral.2022.105453

The prophylactic and therapeutic efficacy of the broadly active antiviral ribonucleoside N⁴-Hydroxycytidine (EIDD-1931) in a mouse model of lethal Ebola virus infection

Antiviral Res. 2023 Jan:209:105453. doi: 10.1016/j.antiviral.2022.105453. Epub 2022 Nov 13.

Affiliations

¹ 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.
² Emory Institute for Drug Development (EIDD), 954 North Gatewood Road NE, Atlanta, GA, 30329, USA.
³ Ridgeback Biotherapeutics, LP, 3480 Main Highway, Unit 402, Miami, FL, 33133, USA.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ 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.

PMID: 36379378
DOI: 10.1016/j.antiviral.2022.105453

Abstract

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 N⁴-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.

Keywords: EIDD-1931; EIDD-2801; Ebola antiviral; Molnupiravir; N(4)-hydroxycytidine; Ribonucleoside analog.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antiviral Agents / pharmacology
Antiviral Agents / therapeutic use
Ebolavirus*
Hemorrhagic Fever, Ebola* / drug therapy
Hemorrhagic Fever, Ebola* / prevention & control
Mice
Ribonucleosides* / pharmacology

Substances

molnupiravir
N(4)-hydroxycytidine
Antiviral Agents
Ribonucleosides