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Peer-reviewedCC BY 4.0Antimicrobial Agents and Chemotherapy

Oral lipid prodrug V2043 (1-O-octadecyl-2-O-benzyl-sn-glyceryl-P-remdesivir nucleoside) protects mice from lethal dengue infection

  • Alex E. Clark1,2
  • Jonathan R. Erlich3,4
  • James R. Beadle2
  • Rachel E. McMillan2
  • Jialei Xie1,2
  • Aaron F. Garretson1,2
  • Shae Atkins1
  • Anoushka Sharma1
  • Suraj Manohar Rajan1
  • Ben A. Croker3
  • Robert T. Schooley2
  • Karl Y. Hostetler2
1 more authors
  • Aaron F. Carlin1,2
4 affiliations
  1. 1Department of Pathology, University of California San Diego, La Jolla, California, USA
  2. 2Department of Medicine, University of California San Diego, La Jolla, California, USA
  3. 3Department of Pediatrics, University of California San Diego, La Jolla, California, USA
  4. 4Department of Infectious Diseases, J. Craig Venter Institute, La Jolla, California, USA
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Abstract

Dengue virus and related flaviviruses are significant threats to global health, with no approved antiviral treatments available. Remdesivir triphosphate (RVn-TP) is a nucleotide analog that inhibits RNA-dependent RNA polymerases from many clinically important RNA viruses, including dengue virus. An orally bioavailable prodrug that efficiently delivers RVn-TP could facilitate early treatment for non-hospitalized dengue patients. To that end, we developed 1-O-octadecyl-2-O-benzyl-sn-glyceryl-P-remdesivir nucleoside (V2043, ODBG-P-RVn), a phospholipid prodrug that achieves RVn-TP delivery through improved oral bioavailability, potency, and pharmacokinetics. Here, we show that when compared to the parent compound remdesivir nucleoside (RVn), V2043 is a more potent in vitro inhibitor of multiple flaviviruses, including dengue, Zika, West Nile, and Japanese encephalitis viruses. In lethal prophylactic and therapeutic mouse models that recapitulate key aspects of severe dengue in humans, once-daily oral V2043 significantly decreased dengue serum viremia, clinical severity, weight loss, and mortality. Additionally, oral V2043 was well tolerated when administered daily for 14 days. These results demonstrate the potential therapeutic efficacy of V2043 to treat several clinically relevant flaviviruses, including dengue virus, the most prevalent and widespread arbovirus infection in the world.

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Cite

BibTeXRIS
BibTeX
@article{clark2026oral,
  title = {{Oral lipid prodrug V2043 (1-O-octadecyl-2-O-benzyl-sn-glyceryl-P-remdesivir nucleoside) protects mice from lethal dengue infection}},
  author = {Alex E. Clark and Jonathan R. Erlich and James R. Beadle and Rachel E. McMillan and Jialei Xie and Aaron F. Garretson and Shae Atkins and Anoushka Sharma and Suraj Manohar Rajan and Ben A. Croker and Robert T. Schooley and Karl Y. Hostetler and Aaron F. Carlin},
  journal = {Antimicrobial Agents and Chemotherapy},
  year = {2026},
  month = aug,
  doi = {10.1128/aac.00401-26},
  url = {https://doi.org/10.1128/aac.00401-26},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Oral lipid prodrug V2043 (1-O-octadecyl-2-O-benzyl-sn-glyceryl-P-remdesivir nucleoside) protects mice from lethal dengue infection
AU  - Alex E. Clark
AU  - Jonathan R. Erlich
AU  - James R. Beadle
AU  - Rachel E. McMillan
AU  - Jialei Xie
AU  - Aaron F. Garretson
AU  - Shae Atkins
AU  - Anoushka Sharma
AU  - Suraj Manohar Rajan
AU  - Ben A. Croker
AU  - Robert T. Schooley
AU  - Karl Y. Hostetler
AU  - Aaron F. Carlin
PY  - 2026
DA  - 2026/08/03
JO  - Antimicrobial Agents and Chemotherapy
DO  - 10.1128/aac.00401-26
UR  - https://doi.org/10.1128/aac.00401-26
AB  - Dengue virus and related flaviviruses are significant threats to global health, with no approved antiviral treatments available. Remdesivir triphosphate (RVn-TP) is a nucleotide analog that inhibits RNA-dependent RNA polymerases from many clinically important RNA viruses, including dengue virus. An orally bioavailable prodrug that efficiently delivers RVn-TP could facilitate early treatment for non-hospitalized dengue patients. To that end, we developed 1-O-octadecyl-2-O-benzyl-sn-glyceryl-P-remdesivir nucleoside (V2043, ODBG-P-RVn), a phospholipid prodrug that achieves RVn-TP delivery through improved oral bioavailability, potency, and pharmacokinetics. Here, we show that when compared to the parent compound remdesivir nucleoside (RVn), V2043 is a more potent in vitro inhibitor of multiple flaviviruses, including dengue, Zika, West Nile, and Japanese encephalitis viruses. In lethal prophylactic and therapeutic mouse models that recapitulate key aspects of severe dengue in humans, once-daily oral V2043 significantly decreased dengue serum viremia, clinical severity, weight loss, and mortality. Additionally, oral V2043 was well tolerated when administered daily for 14 days. These results demonstrate the potential therapeutic efficacy of V2043 to treat several clinically relevant flaviviruses, including dengue virus, the most prevalent and widespread arbovirus infection in the world.
SN  - 0066-4804
SN  - 1098-6596
ER  -