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.

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.

• Authors: Aaron 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 66 Issue 8 Pg. 5802-5819 (04 27 2023) ISSN: 1520-4804 [Electronic] United States
• PMID: 37040439 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Phospholipids
• GS-441524

Topics

• Animals
• Mice
• Antiviral Agents
• SARS-CoV-2
• COVID-19
• Phospholipids