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

1 Scopus citations

Abstract

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
Volume203
DOIs
StatePublished - Jul 2022

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Virology

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