Enhanced broad spectrum in vitro antiviral efficacy of 3-F-4-MeO-Bn, 3-CN, and 4-CN derivatives of lipid remdesivir nucleoside monophosphate prodrugs

McMillan, Rachel E.; Lo, Michael K.; Zhang, Xing-Quan; Beadle, James R.; Valiaeva, Nadejda; Garretson, Aaron F.; Clark, Alex E.; Freshman, Jon E.; Murphy, Joyce; Montgomery, Joel M.; Spiropoulou, Christina F.; Schooley, Robert T.; Hostetler, Karl Y.; Carlin, Aaron F.

doi:10.1016/j.antiviral.2023.105718

Antiviral Research

2023

DOI: 10.1016/j.antiviral.2023.105718

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Enhanced broad spectrum in vitro antiviral efficacy of 3-F-4-MeO-Bn, 3-CN, and 4-CN derivatives of lipid remdesivir nucleoside monophosphate prodrugs

Rachel E. McMillan,

Michael K. Lo,

Xing-Quan Zhang

et al.

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2024

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Cited by 4 publications

References 27 publications

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Meeting report of the 37th International Conference on Antiviral Research in Gold Coast, Australia, May 20–24, 2024, organized by the International Society for Antiviral Research

Welch,

Bilello,

Carter

et al. 2024

Antiviral Research

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Meeting report of the 37th International Conference on Antiviral Research in Gold Coast, Australia, May 20–24, 2024, organized by the International Society for Antiviral Research

Welch,

Bilello,

Carter

et al. 2024

Antiviral Research

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Lipid-conjugated nucleoside monophosphate and monophosphonate prodrugs: A versatile drug delivery paradigm

Zhang,

Fan,

Zhang

et al. 2024

European Journal of Medicinal Chemistry

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

Carlin,

Beadle,

Ardanuy

et al. 2024

Antimicrob Agents Chemother

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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.

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Enhanced broad spectrum in vitro antiviral efficacy of 3-F-4-MeO-Bn, 3-CN, and 4-CN derivatives of lipid remdesivir nucleoside monophosphate prodrugs

Cited by 4 publications

References 27 publications

Meeting report of the 37th International Conference on Antiviral Research in Gold Coast, Australia, May 20–24, 2024, organized by the International Society for Antiviral Research

Meeting report of the 37th International Conference on Antiviral Research in Gold Coast, Australia, May 20–24, 2024, organized by the International Society for Antiviral Research

Lipid-conjugated nucleoside monophosphate and monophosphonate prodrugs: A versatile drug delivery paradigm

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

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