Autor: |
Moreira, F.R., Baric, R.S., Graham, R.L., Beadle, J.R., McVicar, R.N., Rana, T., Zhang, X.-Q., Schooley, R.T., Freshman, J.E., Clark, A.E., Gully, K.L., Murphy, J.A., Carlin, A.F., Valiaeva, N., Leibel, S.L., Bray, W., Garretson, A.F., Hostetler, K.Y., McMillan, R.E. |
Jazyk: |
angličtina |
Rok vydání: |
2023 |
DOI: |
10.17615/zmxg-nk26 |
Popis: |
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. |
Databáze: |
OpenAIRE |
Externí odkaz: |
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