Intravenous delivery of GS-441524 is efficacious in the African green monkey model of SARS-CoV-2 infection

Jared Pitts, Darius Babusis, Meghan S. Vermillion, Raju Subramanian, Kim Barrett, Diane Lye, Bin Ma, Xiaofeng Zhao, Nicholas Riola, Xuping Xie, Adriana Kajon, Xianghan Lu, Roy Bannister, Pei Yong Shi, Maria Toteva, Danielle P. Porter, Bill J. Smith, Tomas Cihlar, Richard Mackman, John P. Bilello

Research output: Contribution to journalArticlepeer-review


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, has infected over 260 million people over the past 2 years. Remdesivir (RDV, VEKLURY®) is currently the only antiviral therapy fully approved by the FDA for the treatment of COVID-19. The parent nucleoside of RDV, GS-441524, exhibits antiviral activity against numerous respiratory viruses including SARS-CoV-2, although at reduced in vitro potency compared to RDV in most assays. Here we find in both human alveolar and bronchial primary cells, GS-441524 is metabolized to the pharmacologically active GS-441524 triphosphate (TP) less efficiently than RDV, which correlates with a lower in vitro SARS-CoV-2 antiviral activity. In vivo, African green monkeys (AGM) orally dosed with GS-441524 yielded low plasma levels due to limited oral bioavailability of <10%. When GS-441524 was delivered via intravenous (IV) administration, although plasma concentrations of GS-441524 were significantly higher, lung TP levels were lower than observed from IV RDV. To determine the required systemic exposure of GS-441524 associated with in vivo antiviral efficacy, SARS-CoV-2 infected AGMs were treated with a once-daily IV dose of either 7.5 or 20 mg/kg GS-441524 or IV RDV for 5 days and compared to vehicle control. Despite the reduced lung TP formation compared to IV dosing of RDV, daily treatment with IV GS-441524 resulted in dose-dependent efficacy, with the 20 mg/kg GS-441524 treatment resulting in significant reductions of SARS-CoV-2 replication in the lower respiratory tract of infected animals. These findings demonstrate the in vivo SARS-CoV-2 antiviral efficacy of GS-441524 and support evaluation of its orally bioavailable prodrugs as potential therapies for COVID-19.

Original languageEnglish (US)
Article number105329
JournalAntiviral research
StatePublished - Jul 2022


  • African green monkey
  • GS-441524
  • Remdesivir
  • SARS-CoV-2

ASJC Scopus subject areas

  • Pharmacology
  • Virology


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