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Enhancing the Antiviral Potency of Nucleobases for Potential Broad-Spectrum Antiviral Therapies.
Soto-Acosta, Ruben; Edwards, Tiffany C; Dreis, Christine D; Krishna, Venkatramana D; Cheeran, Maxim C-J; Qiu, Li; Xie, Jiashu; Bonnac, Laurent F; Geraghty, Robert J.
  • Soto-Acosta R; Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
  • Edwards TC; Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
  • Dreis CD; Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
  • Krishna VD; Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA.
  • Cheeran MC; Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA.
  • Qiu L; Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
  • Xie J; Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
  • Bonnac LF; Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
  • Geraghty RJ; Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
Viruses ; 13(12)2021 12 14.
Article in English | MEDLINE | ID: covidwho-1572668
ABSTRACT
Broad-spectrum antiviral therapies hold promise as a first-line defense against emerging viruses by blunting illness severity and spread until vaccines and virus-specific antivirals are developed. The nucleobase favipiravir, often discussed as a broad-spectrum inhibitor, was not effective in recent clinical trials involving patients infected with Ebola virus or SARS-CoV-2. A drawback of favipiravir use is its rapid clearance before conversion to its active nucleoside-5'-triphosphate form. In this work, we report a synergistic reduction of flavivirus (dengue, Zika), orthomyxovirus (influenza A), and coronavirus (HCoV-OC43 and SARS-CoV-2) replication when the nucleobases favipiravir or T-1105 were combined with the antimetabolite 6-methylmercaptopurine riboside (6MMPr). The 6MMPr/T-1105 combination increased the C-U and G-A mutation frequency compared to treatment with T-1105 or 6MMPr alone. A further analysis revealed that the 6MMPr/T-1105 co-treatment reduced cellular purine nucleotide triphosphate synthesis and increased conversion of the antiviral nucleobase to its nucleoside-5'-monophosphate, -diphosphate, and -triphosphate forms. The 6MMPr co-treatment specifically increased production of the active antiviral form of the nucleobases (but not corresponding nucleosides) while also reducing levels of competing cellular NTPs to produce the synergistic effect. This in-depth work establishes a foundation for development of small molecules as possible co-treatments with nucleobases like favipiravir in response to emerging RNA virus infections.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / RNA Viruses / Antimetabolites Type of study: Prognostic study Topics: Vaccines Limits: Animals / Humans Language: English Year: 2021 Document Type: Article Affiliation country: V13122508

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / RNA Viruses / Antimetabolites Type of study: Prognostic study Topics: Vaccines Limits: Animals / Humans Language: English Year: 2021 Document Type: Article Affiliation country: V13122508