2. Academic Validation
  3. Combinations of approved oral nucleoside analogues confer potent suppression of alphaviruses in vitro and in vivo

Combinations of approved oral nucleoside analogues confer potent suppression of alphaviruses in vitro and in vivo

  • bioRxiv. 2025 Jan 25:2025.01.24.633564. doi: 10.1101/2025.01.24.633564.
Sam Verwimp 1,  Jessica Wagoner 2,  Elijah Gabriela Arenas 2,  Lander De Coninck 3,  Rana Abdelnabi 4 5,  Jennifer L Hyde 6,  Joshua T Schiffer 7 8,  Judith M White 9,  Jelle Matthijnssens 3,  Johan Neyts 4,  Stephen J Polyak 2,  Leen Delang 1
Affiliations

Affiliations

  • 1 Virus-host Interactions & Therapeutic Approaches (VITA) Research Group, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research - KU Leuven, Leuven, Belgium.
  • 2 Department of Laboratory Medicine and Pathology, University of Washington, Seattle, USA.
  • 3 Laboratory of Clinical and Epidemiological Virology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research - KU Leuven, Leuven, Belgium.
  • 4 Virology, Antiviral Drug & Vaccine Research Group, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research - KU Leuven, Leuven, Belgium.
  • 5 VirusBank Platform, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.
  • 6 Department of Microbiology, University of Washington, Seattle, USA.
  • 7 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • 8 Department of Medicine, University of Washington, Seattle, WA, USA.
  • 9 Department of Cell Biology, University of Virginia, Charlottesville, VA, USA.
PMID: 39896535 DOI: 10.1101/2025.01.24.633564
Abstract

Alphaviruses such as chikungunya virus (CHIKV) pose a significant threat to global health, yet specific Antiviral therapies remain unavailable. In this study, we evaluated combinations of three approved oral directly acting Antiviral (DAA) drugs (sofosbuvir (SOF), molnupiravir (MPV) and favipiravir (FAV)) against CHIKV, Semliki Forest virus (SFV), Sindbis virus (SINV), and Venezuelan Equine Encephalitis virus (VEEV) in vitro and in vivo. In human skin fibroblasts, synergistic Antiviral effects were observed for the drug combinations MPV + SOF and FAV + SOF against CHIKV, and for FAV + SOF against SFV. In human liver Huh7 cells, the combinations of FAV + MPV conferred additive to synergistic activity against VEEV and SINV strains, while SOF synergized with FAV against SINV strains. In a mouse model of CHIKV arthritis, MPV improved CHIKV-induced foot swelling and reduced systemic infectious virus titers. Combination treatment with suboptimal doses of MPV and SOF significantly reduced foot swelling and decreased infectious virus titers in serum as compared to single doses of each drug. Sequencing of CHIKV RNA from mouse joint tissue revealed that MPV caused dose-dependent increases in mutations in the CHIKV genome. Upon combination therapy of MPV with SOF, the number of mutations was significantly lower compared to single treatment with several higher doses of MPV. In summary, combining approved oral nucleoside analogs confers potent suppression of multiple alphaviruses in vitro and in vivo with enhanced control of viral genetic evolution in the face of Antiviral drug pressure. These drug combinations may ultimately lead to the development of potent combinations of pan-family alphavirus inhibitors.

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