2. Academic Validation
  3. 1- O-Octadecyl-2- O-benzyl- sn-glyceryl-3- phospho-GS-441524 (V2043). Evaluation of Oral V2043 in a Mouse Model of SARS-CoV-2 Infection and Synthesis and Antiviral Evaluation of Additional Phospholipid Esters with Enhanced Anti-SARS-CoV-2 Activity

1- O-Octadecyl-2- O-benzyl- sn-glyceryl-3- phospho-GS-441524 (V2043). Evaluation of Oral V2043 in a Mouse Model of SARS-CoV-2 Infection and Synthesis and Antiviral Evaluation of Additional Phospholipid Esters with Enhanced Anti-SARS-CoV-2 Activity

  • J Med Chem. 2023 Apr 27;66(8):5802-5819. doi: 10.1021/acs.jmedchem.3c00046.
Aaron F Carlin 1 2,  James R Beadle 1,  Alex E Clark 1,  Kendra L Gully 3,  Fernando R Moreira 3,  Ralph S Baric 3,  Rachel L Graham 3,  Nadejda Valiaeva 1,  Sandra L Leibel 4,  William Bray 4,  Rachel E McMillan 1 2,  Jonathan E Freshman 1 2,  Aaron F Garretson 1 2,  Rachael N McVicar 5,  Tariq Rana 4,  Xing-Quan Zhang 1,  Joyce A Murphy 1,  Robert T Schooley 1,  Karl Y Hostetler 1
Affiliations

Affiliations

  • 1 Department of Medicine, University of California, San Diego, La Jolla, California 92093, United States.
  • 2 Department of Pathology, University of California, San Diego, La Jolla, California 92093, United States.
  • 3 Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 4 Department of Pediatrics, University of California, San Diego, La Jolla, California 92093, United States.
  • 5 Sanford Burnham Prebys Discovery Institute, La Jolla, California 92037, United States.
PMID: 37040439 DOI: 10.1021/acs.jmedchem.3c00046
Abstract

Early Antiviral treatments, including intravenous remdesivir (RDV), reduce hospitalization and severe disease caused by COVID-19. An orally bioavailable RDV analog may facilitate earlier treatment of non-hospitalized COVID-19 patients. Here we describe the synthesis and evaluation of alkyl glyceryl ether phosphodiesters of GS-441524 (RVn), lysophospholipid analogs which allow for oral bioavailability and stability in plasma. Oral treatment of SARS-CoV-2-infected BALB/c mice with 1-O-octadecyl-2-O-benzyl-sn-glyceryl-3-phospho-RVn (60 mg/kg orally, once daily for 5 days starting 12h after Infection) reduced lung viral load by 1.5 log10 units versus vehicle at day 2 and to below the limit of detection at day 5. Structure/activity evaluation of additional analogs that have hydrophobic ethers at the sn-2 of glycerol revealed improved in vitro Antiviral activity by introduction of a 3-fluoro-4-methoxy-substituted benzyl or a 3- or 4-cyano-substituted benzyl. Collectively, our data support the development of RVn phospholipid prodrugs as oral Antiviral agents for prevention and treatment of SARS-CoV-2 infections.

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