Atea Pharmaceuticals, Inc., Boston, Massachusetts, USA
Department of Animal, Dairy & Veterinary Sciences, Utah State University, Logan, Utah, USA.
Antimicrob Agents Chemother. 2021 Mar 18;65(4). doi: 10.1128/AAC.02479-20.
The impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, is global and unprecedented. Although remdesivir has recently been approved by the FDA to treat SARS-CoV-2 infection, no oral antiviral is available for outpatient treatment. AT-527, an orally administered double prodrug of a guanosine nucleotide analog, was previously shown to be highly efficacious and well tolerated in hepatitis C virus (HCV)-infected subjects. Here, we report the potent activity of AT-511, the free base of AT-527, against several coronaviruses, including SARS-CoV-2. In normal human airway epithelial cells, the concentration of AT-511 required to inhibit replication of SARS-CoV-2 by 90% (EC) was 0.47 μM, very similar to its EC against human coronavirus (HCoV)-229E, HCoV-OC43, and SARS-CoV in Huh-7 cells. Little to no cytotoxicity was observed for AT-511 at concentrations up to 100 μM. Substantial levels of the active triphosphate metabolite AT-9010 were formed in normal human bronchial and nasal epithelial cells incubated with 10 μM AT-511 (698 ± 15 and 236 ± 14 μM, respectively), with a half-life of at least 38 h. Results from steady-state pharmacokinetic and tissue distribution studies of nonhuman primates administered oral doses of AT-527, as well as pharmacokinetic data from subjects given daily oral doses of AT-527, predict that twice daily oral doses of 550 mg AT-527 will produce AT-9010 trough concentrations in human lung that exceed the EC observed for the prodrug against SARS-CoV-2 replication. This suggests that AT-527 may be an effective treatment option for COVID-19.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）是导致 COVID-19 的病原体，其影响是全球性的且前所未有的。虽然瑞德西韦最近已被 FDA 批准用于治疗 SARS-CoV-2 感染，但尚无用于门诊治疗的口服抗病毒药物。AT-527 是一种口服双前药核苷酸类似物，先前已证明在感染丙型肝炎病毒（HCV）的受试者中具有高度疗效和良好的耐受性。在这里，我们报告了 AT-511（AT-527 的游离碱）对几种冠状病毒的有效活性，包括 SARS-CoV-2。在正常的人呼吸道上皮细胞中，抑制 SARS-CoV-2 复制 90%所需的 AT-511 浓度（EC）为 0.47μM，与它在 Huh-7 细胞中对人类冠状病毒（HCoV）-229E、HCoV-OC43 和 SARS-CoV 的 EC 非常相似。在高达 100μM 的浓度下，几乎没有观察到 AT-511 的细胞毒性。在与 10μM AT-511 孵育的正常人支气管和鼻上皮细胞中，形成了大量的活性三磷酸代谢物 AT-9010（分别为 698±15 和 236±14μM），半衰期至少为 38 小时。在给予口服剂量 AT-527 的非人类灵长类动物的稳态药代动力学和组织分布研究以及给予每日口服剂量 AT-527 的受试者的药代动力学数据的结果表明，每天两次口服 550mg AT-527 将产生在人体肺中的 AT-9010 谷浓度，超过了该前药对 SARS-CoV-2 复制的 EC。这表明 AT-527 可能是 COVID-19 的有效治疗选择。
