N4-Hydroxycytidine/molnupiravir inhibits RNA virus-induced encephalitis by producing less fit mutated viruses.

Autor: Ojha D; Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease, National Institutes of Health, Hamilton, Montana, United States of America., Hill CS; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America., Zhou S; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America., Evans A; Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease, National Institutes of Health, Hamilton, Montana, United States of America., Leung JM; Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease, National Institutes of Health, Hamilton, Montana, United States of America., Schneider CA; Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease, National Institutes of Health, Hamilton, Montana, United States of America., Amblard F; Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America., Woods TA; Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease, National Institutes of Health, Hamilton, Montana, United States of America., Schinazi RF; Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America., Baric RS; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America., Peterson KE; Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease, National Institutes of Health, Hamilton, Montana, United States of America., Swanstrom R; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2024 Sep 30; Vol. 20 (9), pp. e1012574. Date of Electronic Publication: 2024 Sep 30.
DOI: 10.1371/journal.ppat.1012574
Abstrakt: A diverse group of RNA viruses have the ability to gain access to the central nervous system (CNS) and cause severe neurological disease. Current treatment for people with this type of infection is generally limited to supportive care. To address the need for reliable antivirals, we utilized a strategy of lethal mutagenesis to limit virus replication. We evaluated ribavirin (RBV), favipiravir (FAV) and N4-hydroxycytidine (NHC) against La Crosse virus (LACV), which is one of the most common causes of pediatric arboviral encephalitis cases in North America and serves as a model for viral CNS invasion during acute infection. NHC was approximately 3 to 170 times more potent than RBV or FAV in neuronal cells. Oral administration of molnupiravir (MOV), the prodrug of NHC, decreased neurological disease development (assessed as limb paralysis, ataxia and weakness, repeated seizures, or death) by 31% (4 mice survived out of 13) when treatment was started on the day of infection. MOV also reduced disease by 23% when virus was administered intranasally (IN). NHC and MOV produced less fit viruses by incorporating predominantly G to A or C to U mutations. Furthermore, NHC also inhibited virus production of two other orthobunyaviruses, Jamestown Canyon virus and Cache Valley virus. Collectively, these studies indicate that NHC/MOV has therapeutic potential to inhibit viral replication and subsequent neurological disease caused by orthobunyaviruses and potentially as a generalizable strategy for treating acute viral encephalitis.
Competing Interests: I have read the journal’s policy, and the authors of this manuscript have the following competing interests: UNC holds a patent for the use of UMIs in sequencing with R.S. listed as a co-inventor, for which he has received nominal royalties. The remaining authors report no competing interest.
(Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)
Databáze: MEDLINE
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