GS-441524 is Pharmacodynamically Equivalent to Remdesivir and Pharmacokinetically Superior Drug for the Treatment of COVID-19

GS-441524在药效学上与瑞德西韦相当，是治疗COVID-19的药代动力学优越的药物

基本信息

批准号：
10199288
负责人：
CHUN LI
金额：
$ 44.2万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199288
关键词：
2019-nCoV Adenosine Animals Antiviral Agents Biochemical Blood Circulation COVID-19 COVID-19 patient COVID-19 treatment Carboxylesterase 1 Cell Line Cell membrane Cells Clinical Data Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats DNA-Directed RNA Polymerase Data Disease Dose Drug Delivery Systems Drug Kinetics Drug or chemical Tissue Distribution Environment Enzymes Epidemic Epithelial Cells Excision Exhibits Feline Coronavirus Felis catus GS-441524 Generations Goals Harvest Hepatocyte Hour Human Hydrolysis In Vitro Injections Inpatients Intravenous Knock-out Lung Manufactured Supplies Maximum Tolerated Dose Modeling Molecular Mus Nucleosides Nucleotidases Nucleotides Organ Parents Pharmaceutical Preparations Pharmacodynamics Pharmacotherapy Phosphoric Monoester Hydrolases Phosphotransferases Prodrugs Production Proxy RNA-Directed RNA Polymerase Review Literature Route SARS-CoV-2 inhibitor Safety Serum System Testing Therapeutic Time Tissues Toxic effect anti-viral efficacy base carboxylesterase cell determination cell immortalization cell type cytotoxicity design esterase experimental study human coronavirus in vivo inhibitor/antagonist inorganic phosphate mouse model nonhuman primate nucleoside analog nucleotide analog overexpression pandemic disease phase 1 study pre-clinical premature prophylactic remdesivir subcutaneous tripolyphosphate

项目摘要

ABSTRACT. Covid-19 is a once in a generation epidemic that has had dire, destabilizing impacts across the world. While remdesivir has emerged as the only drug with proven efficacy, its widespread distribution has been plagued by supply-shortages. Careful review of pre-clinical data evidence that these problems largely derive from the poorly optimized phosphate pro-drug moieties on remdesivir, which ultimately make manufacturing remdesivir more difficult. Careful review of the literature indicates that, its parent nucleoside, GS-441524, is likely the more optimal Covid-19 drug. We hypothesize that GS-441524 is pharmacodynamically equivalent drug to remdesivir, in its ability to generate active nucleotide triphosphate to inhibit the SARS-CoV-2 RNA polymerase. In addition to GS-441524 being significantly easier to synthesize, we contend that its direct administration would enable homogenous tissue distribution of active nucleotide triphosphate inhibitor compared to remdesivir; higher levels of inhibitor would ultimately be achieved in lung epithelial cells most afflicted by SARS-CoV-2. This proposal will make fundamental biochemical advances at the in vitro level and therapeutic advancements at the in vivo level. We will compare the rates bioactivation of GS-4441524 and remdesivir across a broad panel of primary human cell types and delineate the exact molecular mechanism and enzymes which bio-transform remdesivir and GS-441524 into the active triphosphate species. At the same time, we will establish pharmacodynamic equivalence between GS-441524 and remdesivir in mice and non-human primates. Finally, we will demonstrate that GS-441524 is ultimately superior to remdesivir in vivo for generating active triphosphate inhibitor, when each is administered at their maximum tolerated doses. Should our hypotheses prove correct, these data will support GS-441524 for IND and clinical trials.

抽象的。 Covid-19 是一代人一次的流行病，对整个世界造成了可怕的、破坏稳定的影响世界。虽然瑞德西韦已成为唯一被证明有效的药物，但其广泛分布受到供应短缺的困扰。仔细审查临床前数据证据表明这些问题很大程度上源于来自瑞德西韦上优化不佳的磷酸盐前药部分，最终导致制造瑞德西韦更难。仔细查阅文献表明，其母体核苷 GS-441524 很可能更理想的 Covid-19 药物。我们假设 GS-441524 是药效学上等效的药物瑞德西韦能够产生活性三磷酸核苷酸来抑制 SARS-CoV-2 RNA 聚合酶。除了 GS-441524 明显更容易合成之外，我们认为直接给药将与瑞德西韦相比，活性三磷酸核苷酸抑制剂能够均匀分布在组织中；更高最终，受 SARS-CoV-2 影响最严重的肺上皮细胞将达到抑制剂水平。该提案将在体外水平和治疗方面取得根本性的生化进展在体内水平。我们将在广泛的范围内比较 GS-4441524 和瑞德西韦的生物激活率原代人类细胞类型并描述生物转化的确切分子机制和酶瑞德西韦和 GS-441524 转化为活性三磷酸盐。同时，我们将建立 GS-441524 和瑞德西韦在小鼠和非人类灵长类动物中的药效学等效性。最后，我们将证明 GS-441524 在体内生成活性三磷酸方面最终优于瑞德西韦抑制剂，当每种药物以其最大耐受剂量给药时。如果我们的假设被证明是正确的这些数据将支持 GS-441524 的 IND 和临床试验。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Test of 5- Versus 10-Day Remdesivir Treatment in Immunocompromised Patients With Coronavirus Disease 2019.

对患有 2019 年冠状病毒病的免疫功能低下患者进行 5 天与 10 天瑞德西韦治疗的测试。

DOI：
发表时间：
2023-03-21
期刊：
影响因子：
0
作者：
Yan; Victoria C
通讯作者：
Victoria C

Pharmacokinetics of Orally Administered GS-441524 in Dogs.

狗口服 GS-441524 的药代动力学。

DOI：
发表时间：
2021-05-31
期刊：
影响因子：
0
作者：
Yan, Victoria C;Pham, Cong;Yan, Matthew J;Yan, Alexander J;Khadka, Sunada;Arthur, Kenisha;Ackroyd, Jeffrey J;Georgiou, Dimitra K;Roon, Laura E;Bushman, Lane R;Anderson, Peter L;Li, Chun;Muller, Florian L
通讯作者：
Muller, Florian L

An Optimized Bioassay for Screening Combined Anticoronaviral Compounds for Efficacy against Feline Infectious Peritonitis Virus with Pharmacokinetic Analyses of GS-441524, Remdesivir, and Molnupiravir in Cats.

通过 GS-441524、Remdesivir 和 Molnupiravir 在猫体内的药代动力学分析，筛选联合抗冠状病毒化合物对猫传染性腹膜炎病毒的功效的优化生物测定。