Department of Medicine, University of California, San Diego, La Jolla, California 92093, United States.
Department of Pathology, University of California, San Diego, La Jolla, California 92093, United States.
J Med Chem. 2023 Apr 27;66(8):5802-5819. doi: 10.1021/acs.jmedchem.3c00046. Epub 2023 Apr 11.
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--octadecyl-2--benzyl--glyceryl-3--RVn (60 mg/kg orally, once daily for 5 days starting 12h after infection) reduced lung viral load by 1.5 log 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 -2 of glycerol revealed improved 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.
早期的抗病毒治疗，包括静脉注射瑞德西韦（RDV），可降低 COVID-19 引起的住院和重症疾病。口服生物利用度的 RDV 类似物可能更有利于对非住院 COVID-19 患者进行早期治疗。在这里，我们描述了 GS-441524（RVn）的烷基甘油醚磷酸二酯的合成和评估，RVn 是一种可以口服生物利用度和在血浆中稳定的溶血磷脂类似物。用 1-辛基-2-苄基-3-RVn（60mg/kg，口服，每天一次，共 5 天，从感染后 12 小时开始）治疗感染 SARS-CoV-2 的 BALB/c 小鼠，与载体相比，第 2 天肺病毒载量降低了 1.5 个对数单位，第 5 天病毒载量检测不到。对甘油 -2 位具有疏水醚的其他类似物的结构/活性评估表明，通过引入 3-氟-4-甲氧基取代的苄基或 3-或 4-氰基取代的苄基，抗病毒活性得到了改善。总的来说，我们的数据支持将 RVn 磷脂前药开发为预防和治疗 SARS-CoV-2 感染的口服抗病毒药物。
