Rethinking Remdesivir: Synthesis, Antiviral Activity and Pharmacokinetics of Oral Lipid Prodrugs.
Rethinking Remdesivir: Synthesis, Antiviral Activity and Pharmacokinetics of Oral Lipid Prodrugs.
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重新思考瑞德西韦：口服脂质前药的合成、抗病毒活性和药代动力学。
DOI：
10.1101/2020.08.26.269159
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Hostetler,KarlY
中科院分区：
文献类型：
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作者：
Schooley,RobertT;Carlin,AaronF;Beadle,JamesR;Valiaeva,Nadejda;Zhang,Xing-Quan;Clark,AlexE;McMillan,RachelE;Leibel,SandraL;McVicar,RachaelN;Xie,Jialei;Garretson,AaronF;Smith,VictoriaI;Murphy,Joyce;Hostetler,KarlY
瑞德西韦（RDV；GS-5734）是目前 FDA 批准的唯一用于治疗严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）感染的抗病毒药物。该药物被批准用于因 COVID-19 住院治疗的成人或 12 岁或以上儿童，其基础是加速患有该疾病的住院患者的临床康复。不幸的是，该药物必须静脉注射，仅限于因病情相对较重而需要住院治疗的患者。 RDV 在血浆中也不稳定，并且具有复杂的激活途径，这可能导致其在 SARS-CoV-2 感染的细胞中具有高度可变的抗病毒功效。迫切需要用于早期治疗 SARS-CoV-2 感染的强效口服生物可利用抗病毒药物，其中包括 molnupiravir 和 PF-07321332 在内的几种药物目前正处于临床开发阶段。我们专注于制造简单的、口服生物可利用的瑞德西韦核苷脂质类似物（RVn；GS-441524），通过单步细胞内裂解将其加工成 RVn 单磷酸盐，即活性 RVn 三磷酸盐的前体。除了高口服生物利用度、血浆稳定性和更简单的代谢激活之外，RVn 的新型口服脂质前药在多种细胞类型中具有亚微摩尔抗 SARS-CoV-2 活性，包括 Vero E6、Calu-3、Caco-2、人多能干细胞 (PSC) 衍生的肺细胞和 Huh7.5 细胞。在叙利亚仓鼠中，口服 1-O-十八烷基-2-O-苄基甘油-3-磷酸 RVn (ODBG-P-RVn) 治疗耐受性良好，血浆中的治疗水平高于 SARS-CoV-2 的 90% 有效浓度 (EC90)。结果建议进一步评估作为 SARS-CoV-2 感染的早期口服治疗方法，以尽量减少严重疾病并减少住院治疗。
Remdesivir (RDV; GS-5734) is currently the only FDA-approved antiviral drug for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The drug is approved for use in adults or children 12 years or older who are hospitalized for the treatment of COVID-19 on the basis of an acceleration of clinical recovery for inpatients with this disease. Unfortunately, the drug must be administered intravenously, restricting its use to those requiring hospitalization for relatively advanced disease. RDV is also unstable in plasma and has a complex activation pathway which may contribute to its highly variable antiviral efficacy in SARS-CoV-2-infected cells. Potent orally bioavailable antiviral drugs for early treatment of SARS-CoV-2 infection are urgently needed, and several, including molnupiravir and PF-07321332, are currently in clinical development. We focused on making simple, orally bioavailable lipid analogs of remdesivir nucleoside (RVn; GS-441524) that are processed to RVn monophosphate, the precursor of the active RVn triphosphate, by a single-step intracellular cleavage. In addition to high oral bioavailability, stability in plasma, and simpler metabolic activation, new oral lipid prodrugs of RVn had submicromolar anti-SARS-CoV-2 activity in a variety of cell types, including Vero E6, Calu-3, Caco-2, human pluripotent stem cell (PSC)-derived lung cells, and Huh7.5 cells. In Syrian hamsters, oral treatment with 1-O-octadecyl-2-O-benzyl-glycero-3-phosphate RVn (ODBG-P-RVn) was well tolerated and achieved therapeutic levels in plasma above the 90% effective concentration (EC90) for SARS-CoV-2. The results suggest further evaluation as an early oral treatment for SARS-CoV-2 infection to minimize severe disease and reduce hospitalizations.