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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DOI：
10.1128/aac.01155-21
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发表时间：
2021-09-17
影响因子：
4.9
通讯作者：
Hostetler KY
中科院分区：
文献类型：
--
作者：
Schooley RT;Carlin AF;Beadle JR;Valiaeva N;Zhang XQ;Clark AE;McMillan RE;Leibel SL;McVicar RN;Xie J;Garretson AF;Smith VI;Murphy J;Hostetler KY
Remdesivir（RDV; GS-5734）是目前FDA唯一批准的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岁及以上儿童，其基础是加速该疾病住院患者的临床康复。不幸的是，这种药物必须通过静脉注射给药，限制了其用于那些需要住院治疗相对晚期疾病的人。RDV在血浆中也不稳定，并且具有复杂的活化途径，这可能有助于其在SARS-CoV-2感染的细胞中高度可变的抗病毒效力。目前迫切需要有效的口服生物可利用的抗病毒药物用于SARS-CoV-2感染的早期治疗，包括莫努匹拉韦和PF-07321332在内的几种药物目前正在临床开发中。我们专注于制造简单的、口服生物可利用的瑞德西韦核苷（RVn; GS-441524）的脂质类似物，其通过单步细胞内切割加工成RVn单磷酸，活性RVn三磷酸的前体。除了高口服生物利用度、在血浆中的稳定性和更简单的代谢活化之外，RVn的新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Huh 7.5细胞。在叙利亚仓鼠中，1-O-十八烷基-2-O-苄基-甘油-3-磷酸RVn（ODBG-P-RVn）口服治疗耐受性良好，血浆中达到的治疗水平高于SARS-CoV-2的90%有效浓度（EC 90）。结果表明，进一步评估作为SARS-CoV-2感染的早期口服治疗，以尽量减少严重疾病和减少住院治疗。
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.