<br>用于治疗 COVID-19 的蛋白酶抑制剂药物组合 Paxlovid 的设计、合成和作用机制,Pharmaceutics

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用于治疗 COVID-19 的蛋白酶抑制剂药物组合 Paxlovid 的设计、合成和作用机制
Pharmaceutics ( IF 4.9 ) Pub Date : 2024-02-02 , DOI: 10.3390/pharmaceutics16020217
Miklós Bege _{1,

2,

3} , Anikó Borbás _{1,

2,

4}

Affiliation

由严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 引起的 COVID-19 大流行给医疗保健系统和医学带来了巨大挑战。全球旨在预防和有效治疗 SARS-CoV-2 感染的研究工作的结果是，已经开发出了具有全新作用机制的疫苗和一些针对病毒周期中关键蛋白的小分子抗病毒药物。迄今为止批准用于治疗 COVID-19 的最有效的小分子药物是 PaxlovidTM，它是两种蛋白酶抑制剂尼尔马特韦和利托那韦的组合。 Nirmatrelvir 是 SARS-CoV-2 主要蛋白酶 (Mpro) 的可逆共价拟肽抑制剂，该酶在病毒繁殖中发挥着至关重要的作用。在该组合中，利托那韦作为药代动力学增强剂，它不可逆地抑制负责尼马瑞韦快速代谢的细胞色素CYP3A4酶，从而增加尼马瑞韦的半衰期和生物利用度。在本教程综述中，我们总结了 Paxlovid 的开发和药物化学方面，涵盖蛋白酶抑制剂的演变、nirmatrelvir 的弹头设计、合成和作用机制，以及利托那韦的合成及其 CYP3A4 抑制机制。还概述了 Paxlovid 对新型病毒突变体的功效。

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The Design, Synthesis and Mechanism of Action of Paxlovid, a Protease Inhibitor Drug Combination for the Treatment of COVID-19

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented an enormous challenge to health care systems and medicine. As a result of global research efforts aimed at preventing and effectively treating SARS-CoV-2 infection, vaccines with fundamentally new mechanisms of action and some small-molecule antiviral drugs targeting key proteins in the viral cycle have been developed. The most effective small-molecule drug approved to date for the treatment of COVID-19 is PaxlovidTM, which is a combination of two protease inhibitors, nirmatrelvir and ritonavir. Nirmatrelvir is a reversible covalent peptidomimetic inhibitor of the main protease (Mpro) of SARS-CoV-2, which enzyme plays a crucial role in viral reproduction. In this combination, ritonavir serves as a pharmacokinetic enhancer, it irreversibly inhibits the cytochrome CYP3A4 enzyme responsible for the rapid metabolism of nirmatrelvir, thereby increasing the half-life and bioavailability of nirmatrelvir. In this tutorial review, we summarize the development and pharmaceutical chemistry aspects of Paxlovid, covering the evolution of protease inhibitors, the warhead design, synthesis and the mechanism of action of nirmatrelvir, as well as the synthesis of ritonavir and its CYP3A4 inhibition mechanism. The efficacy of Paxlovid to novel virus mutants is also overviewed.

更新日期：2024-02-03

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