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Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
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N 4 -Hydroxycytidine/Molnupiravir Inhibits RNA-Virus Induced Encephalitis by Producing Mutated Viruses with Reduced

Durbadal Ojha, Collin S Hill, Shuntai Zhou

    Biorxiv : the Preprint Server for Biology
    |September 4, 2023
    PubMed

    Insights

    N4-hydroxycytidine (NHC) and its prodrug molnupiravir (MOV) show promise in treating neurotropic RNA virus infections. These antivirals limit virus replication and reduce neurological disease severity in preclinical models.

    Area of Science:

    • Virology
    • Neuroscience
    • Drug Discovery

    Background:

    • Many RNA viruses can infect the central nervous system (CNS), causing severe neurological diseases with limited treatment options.
    • Current treatments for viral encephalitis primarily involve supportive care, highlighting the need for effective antiviral therapies.

    Purpose of the Study:

    • To identify a generalizable antiviral strategy against neurotropic RNA viruses.
    • To evaluate the efficacy of N4-hydroxycytidine (NHC) and its prodrug molnupiravir (MOV) against La Crosse virus (LACV).

    Main Methods:

    • NHC, ribavirin (RBV), and favipiravir (FAV) were tested in neuronal cells against LACV.
    • MOV was administered orally or intranasally to infected mice.
    • Viral mutations and fitness were analyzed post-treatment.

    Main Results:

    • NHC demonstrated higher potency than RBV or FAV in neuronal cells.
    • Oral MOV reduced LACV-induced neurological disease by 32% and intranasal MOV by 23%.
    • NHC and MOV induced G-to-A or C-to-U mutations, reducing viral fitness and inhibiting other orthobunyaviruses.

    Conclusions:

    • NHC and MOV exhibit broad-spectrum antiviral activity against neurotropic RNA viruses.
    • NHC/MOV represents a potential therapeutic strategy for managing severe neurological diseases caused by these viruses.
    • Further research into NHC/MOV could lead to novel treatments for viral encephalitis and other CNS infections.

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