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.
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.
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DOI：
10.1021/acs.jmedchem.3c00046
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发表时间：
2023-04-27
影响因子：
7.3
通讯作者：
Hostetler, Karl Y.
中科院分区：
文献类型：
--
作者：
Carlin, Aaron F.;Beadle, James R.;Clark, Alex E.;Gully, Kendra L.;Moreira, Fernando R.;Baric, Ralph S.;Graham, Rachel L.;Valiaeva, Nadejda;Leibel, Sandra L.;Bray, William;McMillan, Rachel E.;Freshman, Jonathan E.;Garretson, Aaron F.;McVicar, Rachael N.;Rana, Tariq;Zhang, Xing-Quan;Murphy, Joyce A.;Schooley, Robert T.;Hostetler, Karl Y.
早期的抗病毒治疗，包括静脉注射雷米德韦(RDV)，可以减少住院时间和新冠肺炎引起的严重疾病。口服生物利用型RDV类似物可能有助于非住院新冠肺炎患者的早期治疗。在这里，我们描述了GS-441524(RVN)的烷基甘油基醚磷二酸酯的合成和评价，这是一种允许口服生物利用度和血浆稳定性的溶血磷脂类似物。口服1-O-octadecyl-2-O-benzyl-sn-glyceryl-3-phospho-RVn(60 mg/kg，从感染后12小时开始，每天一次，连续5天)对感染SARS-CoV-2的BALB/c小鼠进行口服治疗，在第2天比赋形剂减少了1.5log10个单位的肺部病毒载量，并在第5天降至检测下限以下。结构/活性评估表明，通过引入3-氟-4-甲氧基取代苯基或3-或4-氰基取代基，其他具有甘油sn-2疏水醚的类似物的体外抗病毒活性得到改善。总的来说，我们的数据支持RVN磷脂前药作为口服抗病毒药物用于预防和治疗SARS-CoV-2感染的开发。
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.
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DOI：
10.1056/nejmoa2116846
发表时间：
2022-01-27
期刊：
The New England journal of medicine
影响因子：
--
作者：
Gottlieb RL;Vaca CE;Paredes R;Mera J;Webb BJ;Perez G;Oguchi G;Ryan P;Nielsen BU;Brown M;Hidalgo A;Sachdeva Y;Mittal S;Osiyemi O;Skarbinski J;Juneja K;Hyland RH;Osinusi A;Chen S;Camus G;Abdelghany M;Davies S;Behenna-Renton N;Duff F;Marty FM;Katz MJ;Ginde AA;Brown SM;Schiffer JT;Hill JA;GS-US-540-9012 (PINETREE) Investigators
通讯作者：
GS-US-540-9012 (PINETREE) Investigators
影响因子：
--
作者：
McCauley, Katherine B;Hawkins, Finn;Kotton, Darrell N
通讯作者：
Kotton, Darrell N
影响因子：
3.5
作者：
Schott, Herbert;Hamprecht, Klaus;Schwendener, Reto A.
通讯作者：
Schwendener, Reto A.
DOI：
10.1056/nejmoa2118542
发表时间：
2022-04-14
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hammond J;Leister-Tebbe H;Gardner A;Abreu P;Bao W;Wisemandle W;Baniecki M;Hendrick VM;Damle B;Simón-Campos A;Pypstra R;Rusnak JM;EPIC-HR Investigators
通讯作者：
EPIC-HR Investigators
影响因子：
17.1
作者：
Schäfer A;Martinez DR;Won JJ;Meganck RM;Moreira FR;Brown AJ;Gully KL;Zweigart MR;Conrad WS;May SR;Dong S;Kalla R;Chun K;Du Pont V;Babusis D;Tang J;Murakami E;Subramanian R;Barrett KT;Bleier BJ;Bannister R;Feng JY;Bilello JP;Cihlar T;Mackman RL;Montgomery SA;Baric RS;Sheahan TP
通讯作者：
Sheahan TP