拓新药业 阿兹夫定
大湿人
2022-02-08 15:37:21
$拓新药业(SZ301089)$ Conspectus
Modified nucleosides show therapeutic promise for antiviral therapies. However, issues including the emergence of drug resistance, toxicity, and coinfections have posed new challenges for nucleoside-based antiviral drug discovery, particularly in the era of the coronavirus disease 2019 (COVID-19) pandemic. Chemical manipulation could impact the antiviral potency, safety, and drug resistance of nucleosides. Generally, modified nucleosides are difficult to recognize by intracellular important enzymes as substrates and thus exhibit low toxicity. 4′-Modified nucleosides represent an important subclass of modified nucleosides for antiviral therapies. To prevent the occurrence of drug resistance, 4′-modified nucleosides should have 3′-OH, which should also be chemically unreactive for proviral DNA biosynthesis. The absence of 3′-OH may explain the occurrence of drug resistance for censavudine. The introduction of 4′-substituents improves enzymatic and acidic stability and makes the nucleosides more lipophilic, thus improving cell permeability and bioavailability. Steric hindrance between the 4′-substituent and 3′-OH changes the furanose conformation to the 3′-endo type, in which the oxygen lone pair on the furanose ring could not form an oxocarbonium ion for glycolysis. Currently, seven 4′-modified nucleoside drug candidates such as azvudine (also known as FNC), islatravir, censavudine, balapiravir, lumicitabine, AL-335, and 4-azidothymidine have progressed into clinical stages for treating viral infections. Of note, FNC was officially approved by NMPA in July 2021 for use in adult patients with high HIV-1 virus loads (nos. H20210035 and H20210036), providing an alternative therapeutic for patients with HIV-1. The long-term cellular retention of FNC suggests its potential as a long-lasting pre-exposure prophylaxis (PrEP) agent for preventing HIV-1 infection. Mechanistically, FNC not only inhibited HIV-1 reverse transcription and replication but also restored A3G expression in peripheral blood CD4+ T cells in HIV-1 patients receiving FNC. The 4′-azido group in azvudine stabilizes the 3′-C-endo (north) conformation by steric effects and the formation of an intramolecular hydrogen bond with the 3′-OH group, thus decreasing the nucleophilicity of 3′-OH. The north conformation may also enhance the phosphorylation efficiency of FNC by cellular kinases. Encouragingly, FNC, islatravir, and balapiravir show promise for the treatment of coronaviruses, of which FNC has advanced to phase 3 clinical trials in different countries to treat patients with COVID-19 (clinical trial numbers: NCT04668235 and NCT04425772). FNC cured the COVID-19 disease in almost all patients and showed better therapeutic efficacy than remdesivir. In this Account, we provide an overview of 4′-modified nucleoside analogs in clinical stages for antiviral therapies, highlighting the drug discovery strategies, structure–activity relationship studies, and preclinical/clinical studies and also give our perspectives on nucleoside-based antiviral drug discovery.
修饰的核苷显示出抗病毒治疗的前景。然而，包括出现耐药性、毒性和合并感染在内的问题给基于核苷的抗病毒药物发现带来了新的挑战，特别是在冠状病毒疾病2019(新冠肺炎)疫情时代。化学操作可能会影响核苷的抗病毒效力、安全性和耐药性。通常，修饰的核苷很难被细胞内重要的酶识别为底物，因此表现出低毒性。4′-修饰核苷是抗病毒治疗中修饰核苷的一个重要亚类。为了防止耐药性的发生，4′-修饰的核苷应该具有3′-OH，该3′-OH对于前体DNA生物合成也应该是化学不反应的。3′-羟基的缺失可以解释香茶菜碱耐药性的产生。4′-取代基的引入提高了酶和酸的稳定性，并使核苷更亲脂性，从而提高了细胞渗透性和生物利用度。4′-取代基和3′-羟基之间的空间位阻使呋喃糖构象变为3′-内型，其中呋喃糖环上的氧孤对不能形成糖酵解的氧碳离子。目前，7种4′-修饰的核苷类候选药物，如阿兹夫定(也称为FNC)、伊斯曲韦、香沙夫定、巴拉匹拉韦、鲁米他滨、AL-335和4-叠氮胸苷，已经进入治疗病毒感染的临床阶段。值得注意的是，NMPA于2021年7月正式批准FNC用于HIV-1病毒载量高的成年患者(编号H20210035和H20210036)，为HIV-1患者提供了一种替代疗法。FNC的长期细胞滞留表明其作为预防HIV-1感染的长期暴露前预防(PrEP)剂的潜力。从机制上讲，FNC不仅抑制了HIV-1逆转录和复制，还恢复了接受FNC治疗的HIV-1患者外周血CD4+ T细胞中A3G的表达。阿兹夫定中的4′-叠氮基通过空间效应和与3′-羟基形成分子内氢键来稳定3′-碳内(北)构象，从而降低3′-羟基的亲核性。north构象也可能增强细胞激酶对FNC的磷酸化效率。令人鼓舞的是，FNC、islatravir和balapiravir显示出治疗冠状病毒的希望，其中FNC已经在不同国家进行了3期临床试验，治疗新冠肺炎患者(临床试验号:NCT04668235和NCT04425772)。FNC治愈了几乎所有患者的新冠肺炎病，并显示出比雷美昔韦更好的治疗效果。在本报告中，我们概述了抗病毒治疗临床阶段的4′-修饰核苷类似物，重点介绍了药物发现策略、构效关系研究和临床前/临床研究，并给出了我们对基于核苷的抗病毒药物发现的观点。
Modified nucleosides show therapeutic promise for antiviral therapies. However, issues including the emergence of drug resistance, toxicity, and coinfections have posed new challenges for nucleoside-based antiviral drug discovery, particularly in the era of the coronavirus disease 2019 (COVID-19) pandemic. Chemical manipulation could impact the antiviral potency, safety, and drug resistance of nucleosides. Generally, modified nucleosides are difficult to recognize by intracellular important enzymes as substrates and thus exhibit low toxicity. 4′-Modified nucleosides represent an important subclass of modified nucleosides for antiviral therapies. To prevent the occurrence of drug resistance, 4′-modified nucleosides should have 3′-OH, which should also be chemically unreactive for proviral DNA biosynthesis. The absence of 3′-OH may explain the occurrence of drug resistance for censavudine. The introduction of 4′-substituents improves enzymatic and acidic stability and makes the nucleosides more lipophilic, thus improving cell permeability and bioavailability. Steric hindrance between the 4′-substituent and 3′-OH changes the furanose conformation to the 3′-endo type, in which the oxygen lone pair on the furanose ring could not form an oxocarbonium ion for glycolysis. Currently, seven 4′-modified nucleoside drug candidates such as azvudine (also known as FNC), islatravir, censavudine, balapiravir, lumicitabine, AL-335, and 4-azidothymidine have progressed into clinical stages for treating viral infections. Of note, FNC was officially approved by NMPA in July 2021 for use in adult patients with high HIV-1 virus loads (nos. H20210035 and H20210036), providing an alternative therapeutic for patients with HIV-1. The long-term cellular retention of FNC suggests its potential as a long-lasting pre-exposure prophylaxis (PrEP) agent for preventing HIV-1 infection. Mechanistically, FNC not only inhibited HIV-1 reverse transcription and replication but also restored A3G expression in peripheral blood CD4+ T cells in HIV-1 patients receiving FNC. The 4′-azido group in azvudine stabilizes the 3′-C-endo (north) conformation by steric effects and the formation of an intramolecular hydrogen bond with the 3′-OH group, thus decreasing the nucleophilicity of 3′-OH. The north conformation may also enhance the phosphorylation efficiency of FNC by cellular kinases. Encouragingly, FNC, islatravir, and balapiravir show promise for the treatment of coronaviruses, of which FNC has advanced to phase 3 clinical trials in different countries to treat patients with COVID-19 (clinical trial numbers: NCT04668235 and NCT04425772). FNC cured the COVID-19 disease in almost all patients and showed better therapeutic efficacy than remdesivir. In this Account, we provide an overview of 4′-modified nucleoside analogs in clinical stages for antiviral therapies, highlighting the drug discovery strategies, structure–activity relationship studies, and preclinical/clinical studies and also give our perspectives on nucleoside-based antiviral drug discovery.
修饰的核苷显示出抗病毒治疗的前景。然而，包括出现耐药性、毒性和合并感染在内的问题给基于核苷的抗病毒药物发现带来了新的挑战，特别是在冠状病毒疾病2019(新冠肺炎)疫情时代。化学操作可能会影响核苷的抗病毒效力、安全性和耐药性。通常，修饰的核苷很难被细胞内重要的酶识别为底物，因此表现出低毒性。4′-修饰核苷是抗病毒治疗中修饰核苷的一个重要亚类。为了防止耐药性的发生，4′-修饰的核苷应该具有3′-OH，该3′-OH对于前体DNA生物合成也应该是化学不反应的。3′-羟基的缺失可以解释香茶菜碱耐药性的产生。4′-取代基的引入提高了酶和酸的稳定性，并使核苷更亲脂性，从而提高了细胞渗透性和生物利用度。4′-取代基和3′-羟基之间的空间位阻使呋喃糖构象变为3′-内型，其中呋喃糖环上的氧孤对不能形成糖酵解的氧碳离子。目前，7种4′-修饰的核苷类候选药物，如阿兹夫定(也称为FNC)、伊斯曲韦、香沙夫定、巴拉匹拉韦、鲁米他滨、AL-335和4-叠氮胸苷，已经进入治疗病毒感染的临床阶段。值得注意的是，NMPA于2021年7月正式批准FNC用于HIV-1病毒载量高的成年患者(编号H20210035和H20210036)，为HIV-1患者提供了一种替代疗法。FNC的长期细胞滞留表明其作为预防HIV-1感染的长期暴露前预防(PrEP)剂的潜力。从机制上讲，FNC不仅抑制了HIV-1逆转录和复制，还恢复了接受FNC治疗的HIV-1患者外周血CD4+ T细胞中A3G的表达。阿兹夫定中的4′-叠氮基通过空间效应和与3′-羟基形成分子内氢键来稳定3′-碳内(北)构象，从而降低3′-羟基的亲核性。north构象也可能增强细胞激酶对FNC的磷酸化效率。令人鼓舞的是，FNC、islatravir和balapiravir显示出治疗冠状病毒的希望，其中FNC已经在不同国家进行了3期临床试验，治疗新冠肺炎患者(临床试验号:NCT04668235和NCT04425772)。FNC治愈了几乎所有患者的新冠肺炎病，并显示出比雷美昔韦更好的治疗效果。在本报告中，我们概述了抗病毒治疗临床阶段的4′-修饰核苷类似物，重点介绍了药物发现策略、构效关系研究和临床前/临床研究，并给出了我们对基于核苷的抗病毒药物发现的观点。
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