Oral pharmacokinetics and efficacy of oral phospholipid remdesivir nucleoside prodrugs against SARS-CoV-2 in mice

  • Antimicrob Agents Chemother. 2024 Oct 8;68(10):e0103924. doi: 10.1128/aac.01039-24.
Aaron F Carlin  1  2 ,  James R Beadle  2 ,  Jeremy Ardanuy  3  4 ,  Alex E Clark  1  2 ,  Victoria Rhodes  3  4 ,  Aaron F Garretson  1  2 ,  Joyce A Murphy  2 ,  Nadejda Valiaeva  2 ,  Robert T Schooley  2 ,  Matthew B Frieman  3  4 ,  Karl Y Hostetler  2
Affiliations
  • 1. Department of Pathology, University of California San Diego, La Jolla, California, USA.
  • 2. Department of Medicine, University of California San Diego, La Jolla, California, USA.
  • 3. Department of Microbiology and Immunology, The University of Maryland School of Medicine, Baltimore, Maryland, USA.
  • 4. Center for Pathogen Research, The University of Maryland School of Medicine, Baltimore, Maryland, USA.
PMID: 39240093 DOI: 10.1128/aac.01039-24
Abstract

Oral broad-spectrum antivirals are urgently needed for the treatment of many emerging and contemporary RNA viruses. We previously synthesized 1-O-octadecyl-2-O-benzyl-sn-glyceryl-P-RVn (ODBG-P-RVn, V2043), a phospholipid prodrug of GS-441524 (remdesivir nucleoside, RVn), and demonstrated its in vivo efficacy in a SARS-CoV-2 mouse model. Structure-activity relationship studies focusing on the prodrug scaffold identified two modifications, 3-fluoro-4-methoxy-benzyl (V2053) and 4-cyano-benzyl (V2067), that significantly enhanced the in vitro broad-spectrum Antiviral activity against multiple RNA viruses when compared to V2043. Here, we demonstrate that V2043, V2053, and V2067 are all orally bioavailable, well-tolerated, and achieve high sustained plasma levels after single oral daily dosing. All three phospholipid prodrugs are significantly more active than RVn in vitro and significantly reduce SARS-CoV-2 lung titers in prophylaxis and treatment mouse models of SARS-CoV-2 B.1.351 Infection. On a molar basis, V2043 and V2067 are substantially more active than obeldesivir/GS-5245 and molnupiravir in vivo. Together, these data support the continued development of phospholipid RVn prodrugs for the treatment of SARS-CoV-2 and Other RNA viruses of clinical concern.

Keywords
COVID-19; SARS-CoV-2; antiviral agent; broad spectrum antiviral; in vivo efficacy; lipid prodrug; mouse model; pharmacokinetics; remdesivir; remdesivir nucleoside.
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