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
posted on 2023-04-11, 18:07authored byAaron
F. Carlin, James R. Beadle, Alex E. Clark, Kendra L. Gully, Fernando R. Moreira, Ralph S. Baric, Rachel L. Graham, Nadejda Valiaeva, Sandra L. Leibel, William Bray, Rachel E. McMillan, Jonathan E. Freshman, Aaron F. Garretson, Rachael N. McVicar, Tariq Rana, Xing-Quan Zhang, Joyce A. Murphy, Robert T. Schooley, Karl Y. Hostetler
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.