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
  • 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.