Title：Optimization of the Prodrug Moiety of Remdesivir to Improve Lung Exposure/Selectivity and Enhance Anti-SARS-CoV-2 Activity

标题：优化瑞德西韦的前药基团以提高肺部暴露/选择性并增强抗SARS-CoV-2

期刊： 药物化学杂志

发表日期： 2022年9月22日

DOI： 10.1021/acs.jmedchem.2c00758

作者： 胡红祥，Mohamed Dit Mady Traore，李瑞婷，袁荷宝，何淼，文波，高伟，Colleen B Jonsson，Elizabeth A Fitzpatrick，孙德新

Abstract

The study focuses on optimizing the prodrug moiety of Remdesivir, a nucleotide analog prodrug that inhibits RNA-dependent RNA polymerase, to improve its selective delivery to the lungs. This enhancement aims to increase the drug's efficacy against SARS-CoV-2, the virus responsible for COVID-19.

摘要

本研究集中于优化核苷类似物前药瑞德西韦的前药基团，以提高其选择性递送至肺部。此优化旨在增加药物对抗SARS-CoV-2（COVID-19病毒）的疗效。

Key Findings and Details

1. Prodrug Optimization:

- Remdesivir's original prodrug moiety was modified to enhance its stability and selective activation in lung tissues.

- This optimization aimed to improve drug concentration in the lungs, potentially increasing its antiviral efficacy while reducing systemic exposure and associated side effects.

2. Pharmacokinetic and Pharmacodynamic Studies:

- The new prodrug variants were tested in animal models.

- Results showed improved lung retention and antiviral activity against SARS-CoV-2.

3. Antiviral Efficacy:

- The optimized prodrug demonstrated superior antiviral activity in infected lung tissues compared to the original Remdesivir.

- Enhanced lung selectivity suggests potential for reduced dosing and minimized systemic toxicity.

4. Mechanism of Action:

- The study delves into the mechanism by which the optimized prodrug is preferentially activated in the lungs, leveraging specific enzymatic pathways.

主要发现和细节

1. 前药优化：

- 修改了瑞德西韦的原始前药基团，以提高其在肺组织中的稳定性和选择性激活。

- 该优化旨在提高肺部药物浓度，潜在地增加其抗病毒疗效，同时减少全身暴露和相关副作用。

2. 药代动力学和药效学研究：

- 在动物模型中测试了新的前药变体。

- 结果显示，改良的前药在肺部的保留和抗病毒活性得到了改善。

3. 抗病毒效力：

- 优化后的前药在受感染的肺组织中表现出优于原始瑞德西韦的抗病毒活性。

- 增强的肺选择性表明其具有减少剂量和最小化全身毒性的潜力。

4. 作用机制：

- 研究深入探讨了优化前药在肺部优先激活的机制，利用了特定的酶促途径。

Compounds and CAS Numbers

1. Remdesivir

- CAS: 1809249-37-3

2. GS-441524 (a metabolite of Remdesivir)

- CAS: 1191237-69-0

与瑞德西韦相关的化合物及其CAS号

1. 瑞德西韦 (Remdesivir)

- CAS号: 1809249-37-3

2. GS-441524 (瑞德西韦的代谢产物)

- CAS号: 1191237-69-0