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是一代人的流行病，它具有可怕的，破坏了整个稳定的影响世界。尽管Remdesivir已成为唯一具有证实功效的药物，但其广泛分布一直是受到供应服务的困扰。仔细审查这些问题在很大程度上引起的临床前数据证据从雷德西维尔（Remdesivir）上优化的磷酸盐促毒物部分中的优化磷酸盐部分。 Remdesivir更加困难。对文献的仔细审查表明，其母体核苷GS-441524可能是较最佳的Covid-19药物。我们假设GS-441524是药效上等效的药物 Remdesivir，其能够产生活性核苷酸三磷酸抑制SARS-COV-2 RNA聚合酶。除了GS-441524更容易合成之外，我们认为它的直接管理将会与Remdesivir相比，有活性核苷酸抑制剂的同质组织分布；更高最终将在最受SARS-COV-2折磨的肺上皮细胞中达到抑制剂水平。该建议将在体外和治疗进步上取得基本的生化进步在体内层。我们将比较一个宽面板的GS-4441524和Remdesivir的生物活化率原代人类细胞类型，并描绘出生物转化的精确分子机制和酶 Remdesivir和GS-441524进入活性三磷酸物种。同时，我们将建立小鼠和非人类灵长类动物的GS-441524与Remdesivir之间的药效学等效性。最后，我们将证明GS-441524最终优于体内的remdesivir 抑制剂时，每种都以最大耐受剂量给药。我们的假设应该证明正确吗？这些数据将支持用于IND和临床试验的GS-441524。

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）

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.

DOI：
10.3390/v14112429
发表时间：
2022-11-01
期刊：
Viruses
影响因子：
0
作者：
Cook S;Wittenburg L;Yan VC;Theil JH;Castillo D;Reagan KL;Williams S;Pham CD;Li C;Muller FL;Murphy BG
通讯作者：
Murphy BG

Pharmacokinetics of Orally Administered GS-441524 in Dogs.

狗口服 GS-441524 的药代动力学。

DOI：
10.1101/2021.02.04.429674
发表时间：
2021
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Yan,VictoriaC;Pham,Cong-Dat;Yan,MatthewJ;Yan,AlexanderJ;Khadka,Sunada;Arthur,Kenisha;Ackroyd,JeffreyJ;Georgiou,DimitraK;Roon,LauraE;Bushman,LaneR;Anderson,PeterL;Li,Chun;Muller,FlorianL
通讯作者：
Muller,FlorianL

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。