药学学报

Antiviral drug	Approved year	Summary
M2 ion channel blocker
Amantadine	1968 (USA), 1985 (China)	Inhibit the conduction of proton through ion channels, prevent the process of virus RNA unpacking and releasing, and block the viral replication process; only effective against influenza A; poor tolerance and serious drug resistance; no longer recommended for clinical use
Rimantadine	1993 (USA), 2001 (China)
Neuraminidase inhibitor
Zanamivir	1999 (USA), 2009 (China)	Block the release and spread of progeny virus particles from the host cells to infect the surrounding cells; only effective against influenza A and B; well-tolerated with certain drug resistance but no cross-resistance; core medication for the current treatment of influenza virus
Oseltamivir	1999 (USA), 2001 (China)
Peramivir	2010 (Japan), 2013 (China)
Laninamivir	2010 (Japan)
Hemagglutinin inhibitor
Arbidol	1993 (Russia), 2006 (China)	Prevent the membrane fusion of the virus with the host cell; effective against influenza A and B and shows in vitro activity against some other viruses; few side effects; high safety and is less likely to develop drug resistance
RNA dependent RNA polymerase inhibitor
Favipiravir	2014 (Japan), 2020 (China)	Block the process of virus replication; only effective against influenza A and B but are effective against strains resistant to neuraminidase inhibitors; high safety and well-tolerated; certain broad-spectrum antiviral characteristics
Baloxavir marboxil	2018 (Japan), 2021 (China)
Suraxavir marboxil	2025 (China)
Onradivir	2025 (China)

Antiviral drug

Approved year

Summary

M2 ion channel blocker

Amantadine

1968 (USA), 1985 (China)

Inhibit the conduction of proton through ion channels, prevent the process of virus RNA unpacking and releasing, and block the viral replication process; only effective against influenza A; poor tolerance and serious drug resistance; no longer recommended for clinical use

Rimantadine

1993 (USA), 2001 (China)

Neuraminidase inhibitor

Zanamivir

1999 (USA), 2009 (China)

Block the release and spread of progeny virus particles from the host cells to infect the surrounding cells; only effective against influenza A and B; well-tolerated with certain drug resistance but no cross-resistance; core medication for the current treatment of influenza virus

Oseltamivir

1999 (USA), 2001 (China)

Peramivir

2010 (Japan), 2013 (China)

Laninamivir

2010 (Japan)

Hemagglutinin inhibitor

Arbidol

1993 (Russia), 2006 (China)

Prevent the membrane fusion of the virus with the host cell; effective against influenza A and B and shows in vitro activity against some other viruses; few side effects; high safety and is less likely to develop drug resistance

RNA dependent RNA polymerase inhibitor

Favipiravir

2014 (Japan), 2020 (China)

Block the process of virus replication; only effective against influenza A and B but are effective against strains resistant to neuraminidase inhibitors; high safety and well-tolerated; certain broad-spectrum antiviral characteristics

Baloxavir marboxil

2018 (Japan), 2021 (China)

Suraxavir marboxil

2025 (China)

Onradivir

2025 (China)

Antiviral drug	Approved year	Summary
M2 ion channel blocker
Amantadine	1968 (USA), 1985 (China)	Inhibit the conduction of proton through ion channels, prevent the process of virus RNA unpacking and releasing, and block the viral replication process; only effective against influenza A; poor tolerance and serious drug resistance; no longer recommended for clinical use
Rimantadine	1993 (USA), 2001 (China)
Neuraminidase inhibitor
Zanamivir	1999 (USA), 2009 (China)	Block the release and spread of progeny virus particles from the host cells to infect the surrounding cells; only effective against influenza A and B; well-tolerated with certain drug resistance but no cross-resistance; core medication for the current treatment of influenza virus
Oseltamivir	1999 (USA), 2001 (China)
Peramivir	2010 (Japan), 2013 (China)
Laninamivir	2010 (Japan)
Hemagglutinin inhibitor
Arbidol	1993 (Russia), 2006 (China)	Prevent the membrane fusion of the virus with the host cell; effective against influenza A and B and shows in vitro activity against some other viruses; few side effects; high safety and is less likely to develop drug resistance
RNA dependent RNA polymerase inhibitor
Favipiravir	2014 (Japan), 2020 (China)	Block the process of virus replication; only effective against influenza A and B but are effective against strains resistant to neuraminidase inhibitors; high safety and well-tolerated; certain broad-spectrum antiviral characteristics
Baloxavir marboxil	2018 (Japan), 2021 (China)
Suraxavir marboxil	2025 (China)
Onradivir	2025 (China)

Antiviral drug

Approved year

Summary

M2 ion channel blocker

Amantadine

1968 (USA), 1985 (China)

Rimantadine

1993 (USA), 2001 (China)

Neuraminidase inhibitor

Zanamivir

1999 (USA), 2009 (China)

Oseltamivir

1999 (USA), 2001 (China)

Peramivir

2010 (Japan), 2013 (China)

Laninamivir

2010 (Japan)

Hemagglutinin inhibitor

Arbidol

1993 (Russia), 2006 (China)

RNA dependent RNA polymerase inhibitor

Favipiravir

2014 (Japan), 2020 (China)

Baloxavir marboxil

2018 (Japan), 2021 (China)

Suraxavir marboxil

2025 (China)

Onradivir

2025 (China)

Antiviral drug	Approved year	Summary
Nucleoside analogues
Ribavirin	1986 (USA), ~1990s (China)	Inhibits viral replication through multiple mechanisms; nebulized inhalation therapy in high-risk groups or hospitalized children with RSV infection; side effects are obvious and the risk is relatively high; not recommended for regular use
Monoclonal antibody
Palivizumab	1998 (USA)	Binds to the F (Fusion) protein on the surface of RSV, blocking its ability to fuse with the host cell membrane and thereby preventing viral entry; prevention of severe RSV disease in high-risk infants and children, with chronic lung disease of prematurity, or with significant congenital heart disease; the first choice of prevention but with high cost and narrow application scope

Antiviral drug

Approved year

Summary

Nucleoside analogues

Ribavirin

1986 (USA), ~1990s (China)

Inhibits viral replication through multiple mechanisms; nebulized inhalation therapy in high-risk groups or hospitalized children with RSV infection; side effects are obvious and the risk is relatively high; not recommended for regular use

Monoclonal antibody

Palivizumab

1998 (USA)

Binds to the F (Fusion) protein on the surface of RSV, blocking its ability to fuse with the host cell membrane and thereby preventing viral entry; prevention of severe RSV disease in high-risk infants and children, with chronic lung disease of prematurity, or with significant congenital heart disease; the first choice of prevention but with high cost and narrow application scope

Antiviral drug	Approved year	Summary
Nucleoside analogues
Ribavirin	1986 (USA), ~1990s (China)	Inhibits viral replication through multiple mechanisms; nebulized inhalation therapy in high-risk groups or hospitalized children with RSV infection; side effects are obvious and the risk is relatively high; not recommended for regular use
Monoclonal antibody
Palivizumab	1998 (USA)	Binds to the F (Fusion) protein on the surface of RSV, blocking its ability to fuse with the host cell membrane and thereby preventing viral entry; prevention of severe RSV disease in high-risk infants and children, with chronic lung disease of prematurity, or with significant congenital heart disease; the first choice of prevention but with high cost and narrow application scope

Antiviral drug

Approved year

Summary

Nucleoside analogues

Ribavirin

1986 (USA), ~1990s (China)

Monoclonal antibody

Palivizumab

1998 (USA)

Antiviral drug	Approved year	Summary
3CL protein inhibitor
Atilotrelvir/Ritonavir	2023 (China)	Inhibit the activity of the SARS-CoV-2 3CL protease, which is essential for cleaving viral polyproteins into functional non-structural proteins required for replication; the target is highly conserved in the coronavirus and the development of drug resistance is slow; most of these drugs (except ensitrelvir) are often used in combination with CYP3A4 inhibitor ritonavir to prolong the half-life and reduce the frequency of administration; should be used in the early stage of infection and is prone to drug interactions
Simnotrelvir/Ritonavir	2023 (China)
Nimatrelvir/Ritonavir	2022 (EU), 2022 (China)
Leritrelvir	2023 (China)
Ensitrelvir	2022 (Japan)
Nucleoside analogues
Molnupiravir	2021 (UK), 2022 (China)	Functions as a mutagenic ribonucleoside analogue; its active form is incorporated into viral RNA by RdRp, causing erroneous base pairing during replication and introducing numerous mutations, ultimately leading to error catastrophe and loss of viral infectivity; the target is relatively conservative and maintains a certain activity against the variant strain; more antiviral advantages when used in the early stage of viral infection; the safety still needs further verification, and there are controversies regarding genotoxicity, etc
Remdesivir	2020 (Japan)
Deuremidevir hydrobromide	2023 (China)
Azvudine	2021 (China)
Monoclonal antibody
Amubarvimab/Romlusevimab	2021 (China)	Monoclonal antibodies target specific epitopes, primarily on the viral spike protein; by binding to the spike protein they neutralize the virus by blocking its attachment to the host cell receptor and/or entry into cells; to mitigate the risk of resistance due to viral mutations, "antibody cocktail therapy" is often employed; often used in the early stage of infection and has a significant therapeutic effect, but are usually not suitable for oral administration.; the mutation of the virus has produced more escape effects, reducing or rendering the efficacy of the drugs ineffective; some monoclonal antibody drugs have been discontinued or their authorizations have been revoked
Casirivimab/Imdevimab	2020 (EUA in USA)
Bamlanivimab/Etesevimab	2021 (EUA in USA)
Tixagevimab/Cilgavimab	2021 (EUA in USA)
Sotrovimab	2021 (EUA in USA)

Antiviral drug

Approved year

Summary

3CL protein inhibitor

Atilotrelvir/Ritonavir

2023 (China)

Inhibit the activity of the SARS-CoV-2 3CL protease, which is essential for cleaving viral polyproteins into functional non-structural proteins required for replication; the target is highly conserved in the coronavirus and the development of drug resistance is slow; most of these drugs (except ensitrelvir) are often used in combination with CYP3A4 inhibitor ritonavir to prolong the half-life and reduce the frequency of administration; should be used in the early stage of infection and is prone to drug interactions

Simnotrelvir/Ritonavir

2023 (China)

Nimatrelvir/Ritonavir

2022 (EU), 2022 (China)

Leritrelvir

2023 (China)

Ensitrelvir

2022 (Japan)

Nucleoside analogues

Molnupiravir

2021 (UK), 2022 (China)

Functions as a mutagenic ribonucleoside analogue; its active form is incorporated into viral RNA by RdRp, causing erroneous base pairing during replication and introducing numerous mutations, ultimately leading to error catastrophe and loss of viral infectivity; the target is relatively conservative and maintains a certain activity against the variant strain; more antiviral advantages when used in the early stage of viral infection; the safety still needs further verification, and there are controversies regarding genotoxicity, etc

Remdesivir

2020 (Japan)

Deuremidevir hydrobromide

2023 (China)

Azvudine

2021 (China)

Monoclonal antibody

Amubarvimab/Romlusevimab

2021 (China)

Monoclonal antibodies target specific epitopes, primarily on the viral spike protein; by binding to the spike protein they neutralize the virus by blocking its attachment to the host cell receptor and/or entry into cells; to mitigate the risk of resistance due to viral mutations, "antibody cocktail therapy" is often employed; often used in the early stage of infection and has a significant therapeutic effect, but are usually not suitable for oral administration.; the mutation of the virus has produced more escape effects, reducing or rendering the efficacy of the drugs ineffective; some monoclonal antibody drugs have been discontinued or their authorizations have been revoked

Casirivimab/Imdevimab

2020 (EUA in USA)

Bamlanivimab/Etesevimab

2021 (EUA in USA)

Tixagevimab/Cilgavimab

2021 (EUA in USA)

Sotrovimab

2021 (EUA in USA)

Antiviral drug	Approved year	Summary
3CL protein inhibitor
Atilotrelvir/Ritonavir	2023 (China)	Inhibit the activity of the SARS-CoV-2 3CL protease, which is essential for cleaving viral polyproteins into functional non-structural proteins required for replication; the target is highly conserved in the coronavirus and the development of drug resistance is slow; most of these drugs (except ensitrelvir) are often used in combination with CYP3A4 inhibitor ritonavir to prolong the half-life and reduce the frequency of administration; should be used in the early stage of infection and is prone to drug interactions
Simnotrelvir/Ritonavir	2023 (China)
Nimatrelvir/Ritonavir	2022 (EU), 2022 (China)
Leritrelvir	2023 (China)
Ensitrelvir	2022 (Japan)
Nucleoside analogues
Molnupiravir	2021 (UK), 2022 (China)	Functions as a mutagenic ribonucleoside analogue; its active form is incorporated into viral RNA by RdRp, causing erroneous base pairing during replication and introducing numerous mutations, ultimately leading to error catastrophe and loss of viral infectivity; the target is relatively conservative and maintains a certain activity against the variant strain; more antiviral advantages when used in the early stage of viral infection; the safety still needs further verification, and there are controversies regarding genotoxicity, etc
Remdesivir	2020 (Japan)
Deuremidevir hydrobromide	2023 (China)
Azvudine	2021 (China)
Monoclonal antibody
Amubarvimab/Romlusevimab	2021 (China)	Monoclonal antibodies target specific epitopes, primarily on the viral spike protein; by binding to the spike protein they neutralize the virus by blocking its attachment to the host cell receptor and/or entry into cells; to mitigate the risk of resistance due to viral mutations, "antibody cocktail therapy" is often employed; often used in the early stage of infection and has a significant therapeutic effect, but are usually not suitable for oral administration.; the mutation of the virus has produced more escape effects, reducing or rendering the efficacy of the drugs ineffective; some monoclonal antibody drugs have been discontinued or their authorizations have been revoked
Casirivimab/Imdevimab	2020 (EUA in USA)
Bamlanivimab/Etesevimab	2021 (EUA in USA)
Tixagevimab/Cilgavimab	2021 (EUA in USA)
Sotrovimab	2021 (EUA in USA)

Antiviral drug

Approved year

Summary

3CL protein inhibitor

Atilotrelvir/Ritonavir

2023 (China)

Simnotrelvir/Ritonavir

2023 (China)

Nimatrelvir/Ritonavir

2022 (EU), 2022 (China)

Leritrelvir

2023 (China)

Ensitrelvir

2022 (Japan)

Nucleoside analogues

Molnupiravir

2021 (UK), 2022 (China)

Remdesivir

2020 (Japan)

Deuremidevir hydrobromide

2023 (China)

Azvudine

2021 (China)

Monoclonal antibody

Amubarvimab/Romlusevimab

2021 (China)

Casirivimab/Imdevimab

2020 (EUA in USA)

Bamlanivimab/Etesevimab

2021 (EUA in USA)

Tixagevimab/Cilgavimab

2021 (EUA in USA)

Sotrovimab

2021 (EUA in USA)

经呼吸道感染病毒的防治药物研究进展

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张润泽 , 钟武 ^*

药学学报 | 综述 2025,60(8): 2440-2452

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药学学报 |综述 2025 , 60 (8) : 2440 -2452

经呼吸道感染病毒的防治药物研究进展

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张润泽, 钟武^*

作者信息

国家应急防控药物工程技术研究中心, 北京 100850

通讯作者:

钟武, Tel: 86-10-66932624, E-mail: zhongwu@bmi.ac.cn

作者简介:

作者贡献:

张润泽负责文献检索和文章撰写; 钟武对论文进行设计、整体指导和修改。所有作者阅读并认可终稿。

Research progress on preventive and therapeutic drugs for viruses causing respiratory infections

Run-ze ZHANG, Wu ZHONG^*

Affiliations

National Engineering Research Center for the Emergency Drug, Beijing 100850, China

出版时间: 2025-08-12 doi: 10.16438/j.0513-4870.2025-0552

文章导航

摘要

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呼吸道传播是病毒引发人类疾病的常见致病途径, 具有呼吸道传播能力的病毒通常表现出周期性和季节性的流行特征。由于病毒种类繁多, 且不同病毒在结构和生命周期上存在显著差异, 针对各类病毒的防治药物相对匮乏、疗效有限。近年来, 在抗病毒药物的重定位、高通量筛选及基于配体结构的药物分子设计领域取得了显著进展, 本文对几种主要通过呼吸道感染病毒所对应的已批准上市药物进行了归纳总结, 并对当前处于临床试验及研发阶段的抗病毒药物的最新研究进展进行回顾与简述, 旨在为抗病毒药物研发提供参考依据。

关键词

抗病毒药物 / 呼吸道感染 / 药物治疗 / 小分子药物 / 病毒感染 / 临床试验

Abstract

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Viruses infect humans and cause diseases through respiratory transmission, which is the most common pathogenic route for viruses. Viruses with respiratory transmission capabilities typically exhibit periodic and seasonal epidemic characteristics. Due to the wide variety of viruses and significant differences in their structures and life cycles, effective prevention and treatment drugs for various viruses are relatively scarce and have limited efficacy. In recent years, significant progress has been made in the repositioning of antiviral drugs, high-throughput screening and ligand-based drug design. This article systematically summarizes the approved drugs for several major viruses that primarily cause respiratory infections and reviews the latest research progress of antiviral drugs currently in clinical trials, aiming to provide a reference basis for the research and further development of antiviral drugs.

Key words

antiviral drug / respiratory infection / drug therapy / small molecule drug / virus infection / clinical trial

引用本文

张润泽, 钟武. 经呼吸道感染病毒的防治药物研究进展. 药学学报, 2025 , 60 (8) : 2440 -2452 . DOI: 10.16438/j.0513-4870.2025-0552

Run-ze ZHANG, Wu ZHONG. Research progress on preventive and therapeutic drugs for viruses causing respiratory infections[J]. Acta Pharmaceutica Sinica, 2025 , 60 (8) : 2440 -2452 . DOI: 10.16438/j.0513-4870.2025-0552

正文

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呼吸道感染病毒是一类易通过空气传播并经呼吸道感染人类的病原体, 主要包括流感病毒(influenza virus, IFV)、呼吸道合胞病毒(respiratory syncytial virus, RSV)、鼻病毒(human rhinovirus, HRV)、副流感病毒(human parainfluenza virus, HPIV)、腺病毒(human adenovirus, HAdV)、新型冠状病毒(SARS-CoV-2)、博卡病毒(human bocavirus, HBoV)、偏肺病毒(human metapneumovirus, HMPV) 等, 此类病毒变异性、传染性强, 容易引起暴发性流行。人感染后主要表现鼻咽部不适和疼痛、咳嗽、发热等常见的上呼吸道感染症状, 严重时可诱发支气管炎、肺炎、慢性阻塞性肺部疾病等急性下呼吸道感染(acute lower respiratory infections, ALRIs) 症状^{[1, 2]}。全球疾病负担研究2021 (Global Burden of Disease Study 2021) 的研究成果于2024年4月发布, 结果显示2021年由SARS-CoV-2引起的新冠肺炎(COVID-19) 成为全球第2大死因, ALRIs由2019年的第4位下降至第7位, 在中低收入国家ALRIs是患者住院和院内死亡的主要原因^{[3, 4]}。

经呼吸道感染病毒在中国的流行情况与全球趋势基本一致, 但由于中国人口密度高、气候多样性和医疗资源分布不均等因素, 其传播和感染风险更为复杂^[5]。由中国疾病预防控制中心发起的一项监测项目自2009年起对全国24个省份共108家哨点医院的ALRIs患者情况进行监控与分析, 在对近3万份样本进行分析后发现RSV的发病率(9.9%) 位居首位, IFV (6.6%)、HRV (4.8%)、HAdV (3.4%) 等病毒均有较高的发病率。RSV感染多发于2岁以下的儿童, 而IFV等感染多见于成人或老年人, 患者感染后常因ALRIs住院治疗, 具有较高的发病率和死亡率(图1)^[6]。

目前经呼吸道感染病毒的治疗发展受限于对此类病毒本身的研究深度, 对于IFV、RSV、SARS-CoV-2等研究较为深入的病毒, 基于病毒结构的研究确定了清晰的作用靶点, 有作用机制成熟的药物上市, 在临床治疗中确诊感染病毒后尽早接受抗病毒药物治疗并配合支持性治疗往往能够取得良好的疗效。而HRV、HPIV及HAdV等病毒研究相对较少, 大部分成年人感染后出现症状较轻能够自愈, 部分病毒的易感人群基数较小, 多为儿童、老年人或免疫缺陷患者, 这使得临床试验难以开展, 抗病毒药物市场规模小, 研发动力不足。本文对抗呼吸道感染病毒已上市药物进行总结与梳理并简述临床试验阶段的主要抗病毒药物(图2) 及其研究进展, 以期对经呼吸道感染病毒的临床药物治疗提供参考。

1　流感病毒

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1.1　流感病毒简介

IFV是正黏病毒科(Orthomyxoviridae) 分节段单链负义RNA病毒, 共有8个RNA节段负责编码10种已知的病毒蛋白^[7], 3个较大的RNA节段编码RNA依赖的RNA聚合酶(RNA dependent RNA polymerase, RdRp) 的3个亚型: 聚合酶酸性蛋白(polymerase acidic protein, PA) 和两个聚合酶碱性蛋白(polymerase basic protein 1 and 2, PB1 and PB2); 中等RNA节段编码核蛋白(nucleoprotein, NP) 以及两个糖蛋白: 血凝素(hemagglutinin, HA) 和神经氨酸酶(neuraminidase, NA)。其中, NP与聚合酶亚型(PA, PB1, PB2) 以及病毒RNA共同形成病毒的核糖核蛋白复合体; 两个较小的RNA节段编码基质蛋白1 (matrix protein 1, M1) 和基质蛋白2 (matrix protein 2, M2), 基质蛋白2也称离子通道蛋白^[8]。根据病毒NP和M1抗原性的不同将IFV分为甲、乙、丙和丁4种类型^{[9, 10]}, 人群对甲型和乙型IFV普遍易感且发病率和死亡率居高不下, 在世界范围内已然成为公共卫生的沉重负担^[11]。接种疫苗仍然是最有效的预防IFV感染策略^{[12, 13]}, 但IFV通过抗原漂移作用使其具有较强的变异性, 常发生免疫逃逸限制了疫苗的保护效力。为了克服疫苗抗病毒策略的局限性和潜在风险, 小分子抗病毒药物以及单克隆抗体(monoclonal antibody, mAb) 等经历了多年的发展目前在临床治疗和疾病预防过程中发挥着重要的作用^[14]。自1968年美国食品药品监督管理局(Food and Drug Administration, FDA) 批准金刚烷胺用于IFV感染治疗之后, 该领域共有11种不同靶点的药物获批上市(表1)。

1.2　在研抗流感病毒药物

1.2.1　BPR3P0128

BPR3P0128 (图3, 1) 是一种以喹啉为母核的新型RdRp抑制剂, 有研究通过以抑制病毒诱导的细胞病变效应为基础的细胞水平大规模抗IFV药物筛选方法(large-scale anti-influenza virus cell-based assay), 对分子库中超过2万个符合条件的小分子化合物进行随机筛选, 确定苗头化合物CSV0C019002 (EC₅₀ = 4.27 μmol·L^-1, A/WSN/33) 对甲型和乙型IFV具有一定的抑制活性。后对这一类化合物进行构效关系研究及结构优化, 最终确定抗IFV最有效的药效团结构。在合成的超过200个化合物中, 确定BPR3P0128具有最优的IFV抑制活性^[15], 与其他IFV聚合酶抑制剂相比具有新颖的化学结构。利用A/WSN/33毒株进行研究发现BPR3P0128具有良好的抑制活性(EC₅₀ = 0.083 ± 0.022 μmol·L^-1, A/WSN/33), 可能是通过靶向PB2亚基抑制IFV的“夺帽机制”实现抗病毒作用。在后续的研究中还发现BPR3P0128具有潜在的SARS-CoV-2抑制活性, 且与瑞德西韦合用时具有协同效应^[16], 目前处于临床前研究阶段。

1.2.2　CC-42344

运用基于结构的药物发现平台技术(structure-based drug discovery platform technology) 发现了一种全新的PB2抑制剂CC-42344^[17], 体外实验表明其对流行性和季节性甲型IFV具有良好的抑制活性, 目前处于Ⅱ期临床试验阶段, 相关报道较少。

1.2.3　昂拉地韦

部分IFV毒株已对利巴韦林等常见的抗病毒药物逐渐产生耐药性, 为解决这一问题许多新结构、新机制的抗IFV药物不断涌现。通过对苗头化合物VX-787进行结构优化, 在嘧啶环的6位引入环丙基提高了与疏水结合口袋的亲和性、在氮杂吲哚环中再引入氮原子改善了化合物的理化性质, 得到高效的甲型IFV PA抑制剂ZSP1273 (图3, 2), 又名昂拉地韦^[18]。研究结果显示昂拉地韦比先导化合物VX-787和阳性药法匹拉韦具有更加显著抑制IFV聚合酶的活性(IC₅₀ = 0.562 ± 0.116 nmol·L^-1), 对甲型IFV多种毒株均具有抑制活性, 包括奥司他韦和巴洛沙韦耐药株等(EC₅₀ = 0.012~0.063 nmol·L^-1)^[18]。作为首款PB2抑制剂该药物填补了靶向IFV聚合酶PB2亚基的临床空白, 克服现有药物的耐药性问题。结合高效的临床试验设计精准选择最优给药剂量, 在临床Ⅱ期试验结果公布后立即启动Ⅲ期临床试验^[19], 昂拉地韦凭借创新的PB2靶点机制、显著的早期症状缓解和病毒清除能力、可控的安全性, 成为抗IFV感染治疗领域的突破性药物。2025年5月22日, 1类新药昂拉地韦片获得国家食品药品监督管理局批准上市, 适用于成人单纯性甲型IFV患者的治疗。

1.2.4　AL-794

AL-794或JNJ-64155806为化合物ALS-033719的口服前药, 能够靶向IFV聚合酶的PA亚基发挥抑制作用, 对甲型、乙型IFV具有作用。2018年开展了一项针对AL-794药代动力学性质、安全性以及耐受性的临床试验, AL-794每日两次给予200毫克剂量(200 mg BID) 能够达到ALS-033719的有效暴露量, 发挥抗病毒效果且耐受性可接受^[20]。临床试验设计受试人群单一, 仅纳入健康男性且样本量较小, 但其在200 mg BID剂量下实现有效暴露且耐受性可接受, 作用机制新颖、抗病毒潜力明确, 该药有望成为抗IFV感染治疗的重要补充, 但在完成Ⅰ期临床试验后未有进一步研究报道。

1.2.5　AVI-7100

AVI-7100 (radavirsen) 是一种磷酸二酰胺吗啉代寡核苷酸(phosphorodiamidate morpholino oligomer, PMO) 结构的药物, 通过靶向IFV负责编码M1和M2蛋白mRNA的共有翻译起始位点, 抑制病毒蛋白的合成。PMOs在结构上与DNA相似, 都具有标准的核酸碱基且PMOs以吗啉基团替代脱氧核糖, 通过磷酸二酯基团连接^[21]。AVI-7100设计用于识别并结合甲型IFV基质片段的特定mRNA序列, 并通过阻止M1和M2转录物的剪接, 空间位阻阻断翻译前mRNA的加工过程^[22]。在一项针对18至60岁健康人群的Ⅰ期临床试验中, 56名受试者接受了不同剂量的AVI-7100静脉注射, 结果显示单次给药(最高8 mg·kg^-1) 及连续5天每日一次的多次给药(8 mg·kg^-1) 方案均表现出良好的安全性和耐受性。目前该化合物在Ⅰ期临床试验后未见后续临床研究验证该药物对IFV感染的实际治疗效果。

1.2.6　MHAA4549A

针对IFV设计的mAb药物也具有较好的抗病毒效果, MHAA4549A是抗IFV IgG1人源化mAb药物, 通过靶向IFV中高度保守的HA颈部区(stalk region) 实现对IFV的中和作用^[23]。2016年开展的Ⅰ期临床试验通过两项随机、双盲、安慰剂对照的单次剂量递增研究, 在健康志愿者群体中对剂量递增及固定高剂量下该药物的安全性进行初步的试验。结果显示该药物具有良好的安全性和耐受性, 单次静脉给药在健康人群中安全窗宽, 耐受性优异, 且不良反应只有轻微头痛。该药物在血浆中的半衰期为23天, 单次给药可覆盖流感病程, 具有阻断病毒融合和抗体依赖的细胞介导的细胞毒作用(antibody-dependent cell-mediated cytotoxicity, ADCC)^[24]。IIa期临床试验通过静脉注射该药物治疗鼻腔接种IFV H3N2的健康志愿者对临床疗效进行试验, 通过整合病毒学、临床症状、免疫反应和PK数据等方面分析确诊感染的受试者, 研究表明总体耐受性良好, 无药物相关严重不良反应或停药事件, 无剂量依赖性。最高剂量3.6 g的MHAA4549A可发挥强效抗病毒活性, 显著减轻病毒载量(98%~100%)、缓解流感样症状^[25]。目前临床治疗重症IFV感染住院患者时仍缺乏有效的方法, 在药物的临床试验阶段应适当向重点人群倾斜, 不断进行剂量优化确保鼻咽部的有效暴露量。通过探索与其他作用机制的药物联用以评估协同作用的效率也是目前药物研发的常用策略, 不但能够弥补单一作用机制药物长期使用而产生的耐药性问题并能够在一定程度上克服病毒不断变异造成的对单一药物敏感性降低的问题。

2　呼吸道合胞病毒

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2.1　呼吸道合胞病毒简介

RSV是副黏病毒科(Paramyxoviridae) 的线性单链负义具有包膜的RNA病毒, 具有A、B两种主要抗原亚型, 其10个基因共编码11个蛋白, 其中有两种参与病毒侵入细胞过程的跨膜蛋白: 附着糖蛋白(G glycoprotein)、融合糖蛋白(F glycoprotein) 分别负责识别吸附和膜融合过程^[26]。在发达国家RSV感染致死率并不高, 然而放眼全球RSV感染却是主要的致死原因之一, 5岁以下的儿童尤其是婴幼儿中发病率和致死率均居高不下^[27]。人感染RSV后有2~8天的潜伏期, 发病后引起上呼吸道感染症状, 严重时可导致下呼吸道的继发感染。在健康人群中RSV感染是典型的自限性疾病, 所以支持治疗或对症治疗是主要治疗方案。目前已经上市的抗RSV药物包括小分子核苷类似物利巴韦林, 以及靶向RSV F蛋白的人源mAb帕丽珠单抗(palivizumab), 利巴韦林由于较为明显的不良反应而不推荐常规使用^[28], 帕丽珠单抗通过结合RSV F蛋白阻断病毒与宿主细胞膜的融合, 从而阻止病毒进入宿主细胞, 目前仍是全球多数指南推荐的高危婴儿RSV预防首选^[29]。mAb药物主要用于预防而非治疗RSV感染, 加之目前帕丽珠单抗仅在美国批准上市, 价格昂贵且适用范围有限, 仍不具备广泛使用的可能(表2)。

2.2　在研抗呼吸道合胞病毒药物

在研抗RSV药物大部分以F蛋白为靶点, 通过抑制F蛋白阻碍病毒包膜与宿主细胞膜融合过程达到抗病毒作用, 包括GS-5806、JNJ-53718678、AK0529等。

2.2.1　GS-5806

GS-5806 (图4, 3) 又名普沙托韦(presatovir) 是一种小分子RSV抑制剂, 能够靶向阻断RSV F蛋白介导的膜融合过程进而阻断病毒的复制, 且对RSV的两个主要亚型均有作用, 其平均EC₅₀ = 0.43 nmol·L^{-1 [30, 31]}。体外实验中, 在HEK293细胞系中表达RSV F蛋白并观察GS-5806对蛋白结构的变化过程, 发现当GS-5806存在时F蛋白的结构变化显著降低, 其通过干预F蛋白结构变化过程阻碍F蛋白发挥作用^[32]。2020年开展了一项针对GS-5806治疗造血干细胞移植患者RSV感染的随机、双盲、安慰剂对照Ⅱ期临床试验, 试验结果显示, 该药物在免疫抑制人群中耐受性良好, 常见不良反应为腹泻、恶心等, 发生率与安慰剂组相当。试验结果分析, 该药物在淋巴细胞减少症的患者组中展现出显著疗效, 且安全性良好^[33]。结合已完成的试验结果进行入组标准的优化和更加合理的终点设计, 有望开展该药物针对特定人群的深入研究。

2.2.2　ALS-8112/ALS-8176

为了确定抗RSV A亚型药物, 有研究对一系列糖基修饰的核苷类似物进行了筛选, 确定了一系列新型的2′-和4′-修饰的核苷类化合物其中就包括ALS-8112 (图4, 4)^[34]。ALS-8112展现出了对RSV两个亚型不同毒株的广谱抗病毒效果^[35], 其通过靶向RSV L蛋白抑制聚合酶的活性, 在酶分析实验中发现ALS-8112的5′端三磷酸形式(ALS-8112-TP) 能够阻断聚合酶活性, 在RNA合成过程中导致链的终止从而实现特定的抗病毒作用。为了改善ALS-8112较差的口服生物利用度, 通过在其核糖的2′, 3′位羟基上形成酯键改善了化合物的药代动力学性质, 得到了化合物ALS-8176 (图4, 5) 又名卢米西他滨(lumicitabine)^[34]。通过一项随机、双盲、安慰剂对照的病毒攻击模型研究评价ALS-8176的临床治疗效果, 试验虽通过接种病毒模拟自然感染, 无法直接推广至婴幼儿或免疫低下人群, 但能够精准控制感染时间、病毒毒株和给药时机, 减少混杂因素。短期用药(5天) 在健康成人群体中安全性良好, 后发现患者体内病毒载量有73%~88%的降低, 受试者临床症状减轻^[36]。该药物在临床试验中展现出了强效的抗病毒活性和临床改善潜力, 采用了负荷剂量给药策略, 具有口服给药优势、高耐药屏障及良好的短期给药安全性, 是否能够在自然感染患者(尤其是婴幼儿和重症免疫抑制患者) 中发挥治疗作用、长期使用是否满足安全性的要求仍需深入研究。

2.2.3　JNJ-53718678

JNJ-53718678 (图4, 6) 是一种小分子吲哚类化合物, 通过靶向RSV F蛋白阻断膜融合过程使病毒分子无法侵入宿主细胞从而实现抗病毒作用^[37]。在随机双盲对照的Ⅰ期临床试验中首次在人体水平对JNJ-53718678的安全性、耐受性以及药代动力学性质进行了评价, 建立了成熟的药代动力学模型对实验参数进行精确的描述, 同时证明了该化合物在多组剂量条件下均具有良好的耐受性和安全性^[38]。在感染RSV的儿童(12~24月龄) 群体中进行的临床试验同样证实了JNJ-53718678具有良好的耐受性, 同时能够显著降低患者体内的病毒载量, 具有良好的抗病毒作用^[39]。该化合物目前已进行至Ⅲ期临床试验, 但相关报道较少。

2.2.4　AK0529

AK0529 (图4, 7) 是一种具有氧杂环丁烷结构的口服RSV F蛋白抑制剂, 能够通过抑制病毒与宿主细胞的融合过程, 阻断病毒进入细胞及后续复制。AK0529在细胞水平展现出优秀的RSV抑制活性(EC₅₀ = 3 nmol·L^-1), 且在试验中展现出对RSV两种亚型的广谱抗病毒活性^[40]。2024年在中国28家医院开展一项多中心、随机、双盲、安慰剂对照临床试验, 研究该药物对确诊感染RSV的1~24个月龄婴幼儿的治疗效果。相比于安慰剂组, AK0529治疗组患者体内病毒载量显著下降, 不良反应包括腹泻、肝酶水平升高和药物性皮疹, 不良反应发生率较低, 但9%的治疗组检测出现了RSV F蛋白耐药突变。试验结果证实AK0529治疗能够快速改善患者的临床症状、显著降低病毒载量^[41]。AK0529作为首个在婴幼儿群体中证实有效的口服抗RSV药物, 其疗效和便利性能够支持进一步研发, 如纳入更广泛群体并优化给药策略和剂量或联合用药的潜力等。

RSV感染经常发生在因基础疾病住院的患者群体中, 作为治疗药物进行试验的对象数量有限, 且RSV缺乏高度保守且易靶向的酶活性位点, 其融合蛋白在感染过程中经历复杂的构象变化, 设计药物需要精准靶向其预融合中间态难度较高。同时RSV感染多为自限性, 轻症患者治疗需求低且重症患者市场规模有限, 研发动力低导致鲜有成熟的药物上市。

3　新型冠状病毒

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3.1　新型冠状病毒简介

近20年来, 冠状病毒曾多次暴发流行引发重大国际公共卫生事件, 是一类单链RNA病毒, 因其包膜表面的刺突蛋白(spike protein, S) 在电镜下呈现类似“皇冠”的形态而得名, 冠状病毒发生基因重组和变异的几率高, 因此具有众多亚型分类^[42]。SARS-CoV-2是冠状病毒科(coronaviridae) 有包膜的线性单股正链RNA β冠状病毒^[43], 病毒基因共编码4种结构蛋白: 核衣壳蛋白(nucleocapsid protein, N)、膜蛋白(membrane protein, M)、包膜蛋白(envelope protein, E) 和S蛋白及三种非结构蛋白^[44]。3C样蛋白酶(3C-like protease, 3CLpro) 和木瓜样蛋白酶(papain-like protease, PLpro) 是SARS-CoV-2病毒多聚蛋白加工过程中发挥重要作用的蛋白酶, 能够分别在多肽的不同位点切割形成不同的病毒蛋白^[45], 3CLpro因具有较多的切割位点和其高度保守的特点而成为抗病毒药物的高效靶点之一^{[46, 47]}。

病毒蛋白可以单独发挥生理作用, 在病毒生命周期特定的环节中构成病毒蛋白复合物, 能够与宿主免疫反应和发病机制中参与的细胞因子相互作用^[48]。SARS-CoV-2不仅导致呼吸道症状还会影响多器官以及中枢神经系统的正常功能, 严重者导致多器官衰竭直至死亡^[49]。新冠病毒感染的治疗药物主要是通过阻碍病毒吸附、进入细胞以及抑制病毒的复制等机制发挥抗病毒作用, 目前共有10种药物或复方药物以及mAb药物已批准上市用于SARS-CoV-2的治疗。4种mAb药物曾被授权紧急使用, 但由于病毒变异等原因疗效降低或对新变异株无效, 部分已不再使用或撤销紧急使用授权(表3)。

3.2　在研抗SARS-CoV-2药物

3.2.1　PF-07817883

在研抗SARS-CoV-2药物绝大多数利用药物重定位策略对已上市药物进行新适应症的临床试验, 新结构药物比例较低。其中PF-07817883又名ibuzatrelvir是以奈玛特韦为起点进行结构优化得到的第二代口服3CLpro抑制剂, 具有更好的代谢稳定性和口服药代动力学性质以及较少的药物相互作用^[50]。PF-07817883在临床治疗中单独使用可达到抗SARS-CoV-2病毒所需的血药浓度, 不需要与细胞色素P450酶抑制剂如利托那韦合用, 简化临床药物治疗方案的同时避免了与其他药物的相互作用^{[50, 51]}。PF-07817883对中东呼吸综合征冠状病毒(middle east respiratory syndrome coronavirus, MERS-CoV) 也具有一定的效果, 通过化合物与M蛋白共结晶的方式观察二者的相互作用结果发现PF-07817883结构中的三氟甲基能够与M蛋白的S2底物结合口袋相结合, 不同种病毒蛋白结构的不同导致结合活性有所不同^[52]。

3.2.2　VIR-7831

索托韦单抗(sotrovimab, VIR-7831) 为靶向SARS-CoV-2病毒S蛋白的人源免疫球蛋白G1抗体, 可通过中和病毒S蛋白受体结合域中高度保守的抗原决定簇实现抗病毒作用。2021年5月被美国授权紧急使用于轻中度COVID-19患者, 欧盟于2021年12月首次批准用于12岁以上青少年及成人的COVID-19治疗^[53]。

4　腺病毒与鼻病毒

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4.1　腺病毒与鼻病毒简介

HAdV是腺病毒科(Adenoviridae) 最常见的一种双链无包膜的DNA病毒, 根据病毒HA特性、致癌潜力、基因分型等因素将HAdV分为7个种(A~G) 和超过100个血清型^{[54, 55]}。HAdV感染健康人群后通常引发自限性的轻度临床症状, 如眼部感染^[56]、上呼吸道感染^[57]或消化道感染等, 但当感染儿童时通常会引发ALRIs甚至继发严重感染^{[58, 59]}。在世界范围内, HAdV-1~HAdV-7是较为常见的血清型, 其中HAdV-4和HAdV-5在人群中的阳性率最高^{[60, 61]}。HAdV对于儿童尤其是免疫缺陷患儿威胁更大, 目前临床治疗中缺乏有效的药物治疗手段, 虽然利巴韦林、西多福韦(cidofovir, 图5, 8) 等抗病毒药物疗效有限且具有一定毒性, 但仍然是治疗HAdV感染、控制病毒复制的标准治疗手段^[62]。

HRV是小RNA病毒科(Picornaviridae) 的一种正义单链RNA病毒, 根据病毒进入宿主细胞介导受体的不同分为A, B和C3种, 分别通过结合细胞间黏附分子-1 (intercellular adhesion molecule 1, ICAM-1)、低密度脂蛋白受体(low-density lipoprotein receptor, LDLR) 和钙黏蛋白相关家族成员-3 (cadherin-related family member 3, CDHR-3) 介导病毒进入宿主细胞内^[63], 且根据病毒表面蛋白的不同区分了超过160个血清型^[64], HRV感染人之后, 常引起类似普通感冒的症状, 如流鼻涕、鼻塞、咽痛和咳嗽等, 但与普通感冒不同的是, HRV感染后容易诱发ALRIs, 对于患有哮喘或慢性阻塞性肺病等慢性肺部疾病的患者来说, HRV感染可能导致更加严重的肺功能减退^[65]。针对HRV感染目前尚无批准使用的治疗方法或疫苗, 现有的治疗手段主要集中于减轻病毒感染所引起的症状, 而不是抑制病毒复制过程。

4.2　在研抗腺病毒药物

西多福韦是一种脱氧胞苷的核酸类似物, 能够抑制三磷酸形式的脱氧胞苷与病毒DNA的结合导致链终止, 发挥抑制病毒复制的作用, 目前被用于抗HAdV治疗。但因细胞摄取能力较差导致细胞内药物浓度较低, 使西多福韦临床使用的疗效十分有限, 体内病毒的清除仍然主要靠宿主的T细胞免疫功能^[66]。由于HAdV DNA复制依赖宿主细胞的DNA聚合酶, 在药物研发中靶向病毒复制机制的药物容易因缺乏选择性而产生严重的毒副作用, 且HAdV血清型较多, 不同类型病毒基因组差异较大, 抗原表位变异率高使得广谱抗病毒药物以及疫苗的设计更加困难。临床上90%的HAdV感染在健康人群中表现为轻度的上呼吸道或消化道感染症状, 属于自愈性较强的自限性疾病, 虽然免疫抑制患者更容易因HAdV感染产生严重的临床症状, 但该人群规模较小使得药物研发动力不足。有研究通过基因编辑技术(clustered regularly interspaced short palindromic repeats/single-guide RNA, CRISPR/sgRNA)、基因组筛选等方法对B组HAdV进行研究, 发现并鉴定了一种在感染HAdV-B的社区获得性肺炎患者中高表达的白细胞黏附因子(leukocyte cell adhesion molecule, ALCAM), 作为一种在病毒感染过程中发挥重要作用的分子, 可能成为抗病毒药物作用的关键靶点, 为后续抗病毒药物的研发提供新的思路^[67]。

4.3　在研抗鼻病毒药物

Vapendavir (图5, 9) 和普可那利(pleconaril, 图5, 10) 是肠病毒衣壳结合抑制剂, 能够通过阻止病毒吸附宿主细胞实现抗病毒作用, 在现有报道中表现出了对肠道病毒和HRV的抗病毒活性^[68], 同时有研究对药物进行结构优化以解决耐药、诱变和细胞色素P450酶相互作用等问题^[69]。通过基于蛋白质结构的药物设计方法设计得到了抗HRV药物芦平曲韦(rupintrivir, 图5, 11), 为广谱3CLpro抑制剂^[70], 在细胞实验中, 芦平曲韦展现出了强效的抗病毒活性, 能够减少由HRV感染引起的白介素释放, 在早期进行的随机、双盲、安慰剂对照试验中, 通过区分预防组与治疗组分别探究药物的作用效果, 结果总体耐受性良好、不良反应发病率较低, 该药物显示出较强的抗病毒活性但并未显著降低感冒的发生率, 试验临床终点未达标^[71]。可能由于该药物仅发挥了抑制病毒复制的功能, 而缺少阻断炎症反应的作用机制, 其靶点蛋白在不同病毒中具有相对的保守性, 有望深入研究作用机制或与其他药物联合使用以实现广谱抗病毒的作用。

5　中药或天然产物中具有抗病毒活性的单体化合物

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近年来中成药的研发在病毒感染的防治领域取得了显著进展, 尤其是在治疗IFV和SARS-CoV-2感染方面积累了丰富的临床与试验经验, 中药或天然产物中所提取的单体化合物也是发现抗病毒药物的重要来源之一, 近些年许多活性单体化合物也被证实具有较好的抗病毒活性。

5.1　三萜类化合物

三萜类化合物是一类天然植物的次级代谢产物, 具有五环三萜疏水骨架, 在植物体内通常发挥着抵抗病原体和食草动物的防御作用^[72]。病毒包膜中的七肽重复序列-2 (heptad repeat-2, HR-2) 是一类病毒融合蛋白中的保守α螺旋结构域, 在病毒融合后期与HR-1形成“发夹三聚体”(trimer-of-hairpins) 并驱动病毒与细胞膜的融合过程^{[73, 74]}。研究发现三萜类化合物[如齐墩果酸(oleanolic acid, OA, 12)、桦木酸(betulinic acid, BA, 13)、刺囊酸(echinocystic acid, EA, 14) 等, 图6] 通过靶向HR-2以“头对头、尾对尾”(head-to-head and tail-to-tail) 的空间取向跨越HR-2表面, 与关键残基形成疏水作用及氢键, 阻断病毒与宿主细胞融合过程从而抑制多种包膜病毒的入侵。研究发现三萜类化合物分别对埃博拉病毒(ebola virus, EBOV)、马尔堡病毒(marburg virus, MARV)、人免疫缺陷病毒(human immunodeficiency virus, HIV) 和甲型IFV均表现出显著的抑制活性。在抗IFV试验中, 有报道OA及其衍生物Y3 (图6, 15) 通过结合IFV膜蛋白HA实现抑制病毒入侵宿主细胞发挥抗病毒作用, Y21 (图6, 16) 是在半乳糖基团引入含有重氮基而形成的三萜类探针化合物, 二者均能够体现较强的IFV抑制活性^[75]。

5.2　黄烷醇类化合物

表没食子儿茶素没食子酸酯(epigallocatechin gallate, EGCG, 图7, 17) 是绿茶中含量最丰富的一类儿茶素(图7, 18), 属于黄烷醇类化合物, 其分子结构中含有8个酚羟基使其具有较强的抗氧化性和多靶点的生物活性, 是绿茶功能性的核心成分^[76]。对EGCG抗IFV感染活性进行体内实验研究发现, EGCG相比于其他儿茶素类化合物具有更强的抗病毒活性, 通过小鼠灌胃给药(40 mg·kg^-1·d^-1) 能够降低IFV H1N1感染BALB/c小鼠体内病毒载量、缓解病毒引起的肺炎症状并且提高整体生存率^[77]。通过对EGCG作用机制研究发现, 其能够通过破坏病毒包膜的完整性抑制病毒粒子与细胞膜的融合过程, 减弱其入侵宿主细胞膜的能力^[78]。

EGCG通过多重机制可以发挥抗SARS-CoV-2的作用, 其通过高亲和力结合病毒刺突蛋白受体结合域, 能够有效地竞争性抑制病毒与宿主细胞血管紧张素转化酶2 (angiotensin converting enzyme 2, ACE2) 受体的结合从而阻断病毒的吸附和入侵过程^[79]。EGCG及其同分异构体能够稳定结合SARS-CoV-2 3CLpro的催化残基, 抑制病毒多蛋白水解过程, 阻断病毒成熟。体外实验证实EGCG在40 μg·mL^-1质量浓度下无细胞毒性, 对病毒3CLpro抑制率在50%以上, 与传统抗病毒药物联合使用能够增强疗效并降低复发风险^[80]。

5.3　麻茜类化合物

麻茜(Zanthoxylum myriacanthum var. Pubescens, Maqian) 是我国西南地区中药经济作物, 麻茜精油(Maqian essential oil, MQEO) 及其主要成分D/L-柠檬烯具有广谱抗病毒和抗炎潜力^[81]。本课题组前期采用MDCK和A549细胞系评估MQEO及D/L-柠檬烯对甲型IFV (H1N1, H3N2)、乙型IFV (B/Lee/40) 和奥司他韦耐药株(PR/8-R292K) 的抑制作用, 体内实验采用BALB/c小鼠致死剂量IFV攻毒模型, 分别以灌胃给药(250 mg·kg^-1) 和滴鼻给药(30 mg·kg^-1) 两种方式连续给药5天, 监测小鼠的生存率、肺病毒载量、炎症因子和病理变化。结果显示MQEO对奥司他韦耐药株的病毒抑制作用(EC₅₀ = 1.87 ± 1.04 μg·mL^-1), 体内实验发现灌胃给药D-柠檬烯和L-柠檬烯分别将小鼠存活率提高至55.56%和60.00%, 治疗组小鼠肺组织病毒载量降低并且抑制肺组织中促炎因子的表达。通过对二者作用机制的研究发现, 二者均能够通过抑制病毒进入宿主细胞后复制阶段发挥作用, 并通过调控宿主基因调节先天免疫通路, 纠正IFV引发的炎症过度激活^[82]。

目前, 国内研究单位对抗病毒中成药的分子机制也积极进行探索, 如抗病毒口服液、复方银花解毒颗粒等药物均通过深入的研究发现其可能的关键作用靶点。在临床试验中也积极以循证医学核心评价标准开展大样本实验。随着分子机制和循证医学的深入研究, 抗病毒中成药在抗IFV感染和新发传染病防治方面逐渐从“辅助用药”到“主流方案”的渐次发展。

6　总结与展望

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经呼吸道传播的病毒是易引起人类大规模流行的重要病原体之一, 以IFV、SARS-CoV-2为主的呼吸道易感病毒往往能够在短时间内大规模流行甚至是演变成全球大流行。经呼吸道传播病毒常会对老年人、儿童、院内患者等免疫力低下的易感人群造成严重的威胁, 部分病毒感染后会引发严重的肺部感染甚至导致死亡, 对公共健康、医疗体系及社会经济造成巨大的影响。目前针对病毒感染的临床药物治疗需求仍未被满足, 传统抗病毒药物研发流程耗时长、成功率低, 不但难以满足临床药物治疗日益增长的需求, 在应对突发病毒流行时力不从心。随着近几年人工智能(artificial intelligence, AI) 领域的迅速发展, AI辅助药物设计(AI drug design, AIDD) 正处于快速演进的关键阶段, 其发展态势展现出强大的内在驱动力与深远的变革潜力。以AlphaFold为代表的蛋白质结构预测工具加速了靶点识别与验证的进程, 推动了对“不可成药”靶点的新策略探索。AI结合高性能计算、深度生成模型等新兴研究方法的出现大幅提升了分子模拟与结合预测的精度和效率, 使虚拟筛选和分子动力学模拟更加可靠, 也能够通过分析海量的实验数据优化临床试验设计, 提高试验成功率和效率。尽管在数据质量、算法泛化和跨学科协作等方面AI辅助药物设计仍存挑战, 但其在提升药物研发效率、降低失败率、拓展可成药空间方面的巨大价值已逐渐成为主流共识。在治疗病毒感染方面, mRNA药物设计领域同样展现出前所未有的活力与颠覆性潜力, 新冠mRNA疫苗的成功不仅以惊人的速度和效力证明了mRNA药物技术平台的可行性, 更拓宽了治疗不同疾病谱系的可能性。在治疗病毒感染方面, 针对IFV、RSV、HIV等传统疫苗研发困难的病原体, 以及应对新发突发传染病的精准治疗能力是mRNA药物的固有优势。在靶向递送、长效表达、生产工艺、免疫原性精细调控等方面仍存在显著挑战, 但其快速开发的潜力、强大的蛋白表达能力以及不断更新迭代的新兴技术, 不断催生新的革命性疗法^[83]。

相对于疫苗的预防作用来说, 小分子抗病毒药物可以直接抑制病毒复制、阻断关键的病毒-宿主相互作用, 无论是否接种过疫苗均可以通过小分子抗病毒药物进行直接的治疗, 优势在于针对病毒感染的早期治疗可以迅速减少病毒载量、缓解临床症状。目前抗病毒药物研究为了避免耐药性、细胞毒性以及追求广谱抗病毒效果, 常常设计针对于病毒的保守靶点如RdRp、3CLpro等关键蛋白。一些经呼吸道传播病毒如HRV、HPIV、HAdV、HBoV和HMPV等往往毒力较弱并不会造成大流行, 目前抗病毒药物研究积极性不高, 处于临床试验中的药物多为免疫刺激剂等辅助治疗药物。部分药物通过药物重定位策略可以实现有限的广谱抗病毒作用, 抗病毒药物研究部分依赖于对病毒本身的基础研究结果, 病毒关键蛋白的研究能够加速抗病毒药物的设计与研究, 对已知病毒进行完整的研究、丰富抗病毒药物库的种类将有益于人类面对未知病毒暴发的潜在风险, 更加高效、科学地面对未知病毒的挑战。

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2025年第60卷第8期

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doi: 10.16438/j.0513-4870.2025-0552

接收时间：2025-05-14
首发时间：2026-09-20
出版时间：2025-08-12

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收稿日期：2025-05-14
修回日期：2025-06-12

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国家应急防控药物工程技术研究中心, 北京 100850

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钟武, Tel: 86-10-66932624, E-mail: zhongwu@bmi.ac.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Antiviral drug	Approved year	Summary
M2 ion channel blocker
Amantadine	1968 (USA), 1985 (China)	Inhibit the conduction of proton through ion channels, prevent the process of virus RNA unpacking and releasing, and block the viral replication process; only effective against influenza A; poor tolerance and serious drug resistance; no longer recommended for clinical use
Rimantadine	1993 (USA), 2001 (China)
Neuraminidase inhibitor
Zanamivir	1999 (USA), 2009 (China)	Block the release and spread of progeny virus particles from the host cells to infect the surrounding cells; only effective against influenza A and B; well-tolerated with certain drug resistance but no cross-resistance; core medication for the current treatment of influenza virus
Oseltamivir	1999 (USA), 2001 (China)
Peramivir	2010 (Japan), 2013 (China)
Laninamivir	2010 (Japan)
Hemagglutinin inhibitor
Arbidol	1993 (Russia), 2006 (China)	Prevent the membrane fusion of the virus with the host cell; effective against influenza A and B and shows in vitro activity against some other viruses; few side effects; high safety and is less likely to develop drug resistance
RNA dependent RNA polymerase inhibitor
Favipiravir	2014 (Japan), 2020 (China)	Block the process of virus replication; only effective against influenza A and B but are effective against strains resistant to neuraminidase inhibitors; high safety and well-tolerated; certain broad-spectrum antiviral characteristics
Baloxavir marboxil	2018 (Japan), 2021 (China)
Suraxavir marboxil	2025 (China)
Onradivir	2025 (China)

Antiviral drug

Approved year

Summary

M2 ion channel blocker

Amantadine

1968 (USA), 1985 (China)

Rimantadine

1993 (USA), 2001 (China)

Neuraminidase inhibitor

Zanamivir

1999 (USA), 2009 (China)

Oseltamivir

1999 (USA), 2001 (China)

Peramivir

2010 (Japan), 2013 (China)

Laninamivir

2010 (Japan)

Hemagglutinin inhibitor

Arbidol

1993 (Russia), 2006 (China)

RNA dependent RNA polymerase inhibitor

Favipiravir

2014 (Japan), 2020 (China)

Baloxavir marboxil

2018 (Japan), 2021 (China)

Suraxavir marboxil

2025 (China)

Onradivir

2025 (China)

Antiviral drug	Approved year	Summary
Nucleoside analogues
Ribavirin	1986 (USA), ~1990s (China)	Inhibits viral replication through multiple mechanisms; nebulized inhalation therapy in high-risk groups or hospitalized children with RSV infection; side effects are obvious and the risk is relatively high; not recommended for regular use
Monoclonal antibody
Palivizumab	1998 (USA)	Binds to the F (Fusion) protein on the surface of RSV, blocking its ability to fuse with the host cell membrane and thereby preventing viral entry; prevention of severe RSV disease in high-risk infants and children, with chronic lung disease of prematurity, or with significant congenital heart disease; the first choice of prevention but with high cost and narrow application scope

Antiviral drug

Approved year

Summary

Nucleoside analogues

Ribavirin

1986 (USA), ~1990s (China)

Monoclonal antibody

Palivizumab

1998 (USA)

Antiviral drug	Approved year	Summary
3CL protein inhibitor
Atilotrelvir/Ritonavir	2023 (China)	Inhibit the activity of the SARS-CoV-2 3CL protease, which is essential for cleaving viral polyproteins into functional non-structural proteins required for replication; the target is highly conserved in the coronavirus and the development of drug resistance is slow; most of these drugs (except ensitrelvir) are often used in combination with CYP3A4 inhibitor ritonavir to prolong the half-life and reduce the frequency of administration; should be used in the early stage of infection and is prone to drug interactions
Simnotrelvir/Ritonavir	2023 (China)
Nimatrelvir/Ritonavir	2022 (EU), 2022 (China)
Leritrelvir	2023 (China)
Ensitrelvir	2022 (Japan)
Nucleoside analogues
Molnupiravir	2021 (UK), 2022 (China)	Functions as a mutagenic ribonucleoside analogue; its active form is incorporated into viral RNA by RdRp, causing erroneous base pairing during replication and introducing numerous mutations, ultimately leading to error catastrophe and loss of viral infectivity; the target is relatively conservative and maintains a certain activity against the variant strain; more antiviral advantages when used in the early stage of viral infection; the safety still needs further verification, and there are controversies regarding genotoxicity, etc
Remdesivir	2020 (Japan)
Deuremidevir hydrobromide	2023 (China)
Azvudine	2021 (China)
Monoclonal antibody
Amubarvimab/Romlusevimab	2021 (China)	Monoclonal antibodies target specific epitopes, primarily on the viral spike protein; by binding to the spike protein they neutralize the virus by blocking its attachment to the host cell receptor and/or entry into cells; to mitigate the risk of resistance due to viral mutations, "antibody cocktail therapy" is often employed; often used in the early stage of infection and has a significant therapeutic effect, but are usually not suitable for oral administration.; the mutation of the virus has produced more escape effects, reducing or rendering the efficacy of the drugs ineffective; some monoclonal antibody drugs have been discontinued or their authorizations have been revoked
Casirivimab/Imdevimab	2020 (EUA in USA)
Bamlanivimab/Etesevimab	2021 (EUA in USA)
Tixagevimab/Cilgavimab	2021 (EUA in USA)
Sotrovimab	2021 (EUA in USA)

Antiviral drug

Approved year

Summary

3CL protein inhibitor

Atilotrelvir/Ritonavir

2023 (China)

Simnotrelvir/Ritonavir

2023 (China)

Nimatrelvir/Ritonavir

2022 (EU), 2022 (China)

Leritrelvir

2023 (China)

Ensitrelvir

2022 (Japan)

Nucleoside analogues

Molnupiravir

2021 (UK), 2022 (China)

Remdesivir

2020 (Japan)

Deuremidevir hydrobromide

2023 (China)

Azvudine

2021 (China)

Monoclonal antibody

Amubarvimab/Romlusevimab

2021 (China)

Casirivimab/Imdevimab

2020 (EUA in USA)

Bamlanivimab/Etesevimab

2021 (EUA in USA)

Tixagevimab/Cilgavimab

2021 (EUA in USA)

Sotrovimab

2021 (EUA in USA)