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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.
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.
Affiliation
  • McMillan RE; Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA, USA; Department of Pathology, University of California San Diego, School of Medicine, La Jolla, CA, USA.
  • Lo MK; Viral Special Pathogens Branch, Centers for Disease Control and Prevention, Department of Health and Human Services, Atlanta, CA, USA.
  • Zhang XQ; Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA, USA.
  • Beadle JR; Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA, USA.
  • Valiaeva N; Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA, USA.
  • Garretson AF; Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA, USA; Department of Pathology, University of California San Diego, School of Medicine, La Jolla, CA, USA.
  • Clark AE; Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA, USA; Department of Pathology, University of California San Diego, School of Medicine, La Jolla, CA, USA.
  • Freshman JE; Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA, USA; Department of Pathology, University of California San Diego, School of Medicine, La Jolla, CA, USA.
  • Murphy J; Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA, USA.
  • Montgomery JM; Viral Special Pathogens Branch, Centers for Disease Control and Prevention, Department of Health and Human Services, Atlanta, CA, USA.
  • Spiropoulou CF; Viral Special Pathogens Branch, Centers for Disease Control and Prevention, Department of Health and Human Services, Atlanta, CA, USA.
  • Schooley RT; Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA, USA.
  • Hostetler KY; Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA, USA.
  • Carlin AF; Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA, USA; Department of Pathology, University of California San Diego, School of Medicine, La Jolla, CA, USA. Electronic address: acarlin@health.ucsd.edu
Antiviral Res ; 219: 105718, 2023 11.
Article in En | MEDLINE | ID: mdl-37758067
ABSTRACT
Broad spectrum oral antivirals are urgently needed for the early treatment of many RNA viruses of clinical concern. We previously described the synthesis of 1-O-octadecyl-2-O-benzyl-glycero-3-phospho-RVn (V2043), an orally bioavailable lipid prodrug of remdesivir nucleoside (RVn, GS-441524) with broad spectrum antiviral activity against viruses with pandemic potential. Here we compared the relative activity of V2043 with new RVn lipid prodrugs containing sn-1 alkyl ether or sn-2 glycerol modifications. We found that 3-F-4-MeO-Bn, 3-CN-Bn, and 4-CN-Bn sn-2 glycerol modifications improved antiviral activity compared to V2043 when tested in vitro against clinically important RNA viruses from 5 virus families. These results support the continued development of V2043 and sn-2 glycerol modified RVn lipid prodrugs for the treatment of a broad range of RNA viruses for which there are limited therapies.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Antiviral Agents / Prodrugs Language: En Journal: Antiviral Res Year: 2023 Document type: Article Affiliation country:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Antiviral Agents / Prodrugs Language: En Journal: Antiviral Res Year: 2023 Document type: Article Affiliation country: