药学学报

Drug	Reported mechanism of action	Original indication	Clinical information	Developer
Ribavirin	RdRp inhibitor	RSV/HCV	Phase 2 NCT04828564	ICN Pharmaceuticals
Favipiravir	RdRp inhibitor	Ebola	Phase 3 NCT04373733 NCT04349241 NCT04529499 et al	Toyama Chemical
Remdesivir	RdRp inhibitor	Ebola	Phase 4 NCT04252664 NCT04257656 NCT04315948	Gilead
Molnupiravir	RdRp inhibitor	Influenza	Obtain FDA EUA	Merck
VV116	RdRp inhibitor		Phase 3 NCT05341609 NCT05242042 NCT05279235	Chinese scientific research team
Penciclovir		Influenza	Preclinical	Novartis
Nitazoxanide	Interferon response	Antiparasitic	Phase 3 NCT04486313 NCT05157269	Romark Laboratories
Azvudine	Interferon response	HIV	Phase 3 NCT04668235 NCT05033145	Zhengzhou University team
Nafamostat	TMPRSS2 inhibitor	Acute kidney injury	Phase 2 NCT04352400 NCT04390594	Shan Chemical Factory
Camostat mesilate	TMPRSS2 inhibitor	Chronic pancreatitis	Phase 3 NCT04657497
Chloroquine / Hydroxychloroquine	Interference with transport and fusion of viruses	Malaria	Several clinical trials ChiCTR2000029609/ NCT04315948 ChiCTR2000029868 ChiCTR2000029803 et al	Bayer
Arbidol	Blocking virus entry by interfering with clathrin	Influenza	Phase 4 NCT04252885 NCT04260594	Moscow-based Masterlek
Apilimod	Lipid kinase inhibitor		Phase 2 NCT04446377
Carrimycin	Blocking virus entry	Mycobacterium tuberculosis	Phase 3 NCT04672564	Chinese Academy of Medical Sciences team
Tetrandrine	Two‐pore channel 2 inhibitor	Sillicosis	Phase 4 NCT04308317
Cepharanthine	Reverse most dysregulated genes and pathways in infected cells	Leukopenia	Phase 2 NCT05398705
E-64d (Aloxistatin)	Cat B/L inhibitor		Preclinical
Lopinavir/Ritonavir	M^pro inhibitor	HIV	Phase 3 NCT04321174 NCT04364022	Abbvie
Boceprevir	M^pro inhibitor	HCV	Preclinical
Suramin	M^pro inhibitor	Antiparasitic	Preclinical
Ebselen	M^pro inhibitor	HIV	Preclinical
GRL-0617	PL^pro inhibitor	SARS-CoV	Preclinical	Peking University team
Carmofur	M^pro inhibitor	Antineoplastic	Preclinical
Calpeptin	M^pro inhibitor	Calpain inhibitor	Preclinical
Pelitinib	M^pro inhibitor	Non-small-cell lung cancer	Preclinical	Wyeth
Darunavir	M^pro inhibitor	HIV	Preclinical	Tibotec
Sabizabulin		Prostatic cancer	Phase 3 NCT04842747	Veru
Proxalutamide	AR inhibitor	Prostatic cancer	Phase 3 NCT04728802 NCT04853134 NCT04870606 et al	Kintor
HC-1119	AR inhibitor	Prostatic cancer	Phase 3 NCT04986176	Hinova

Drug	Reported mechanism of action	Original indication	Clinical information	Developer
Ribavirin	RdRp inhibitor	RSV/HCV	Phase 2 NCT04828564	ICN Pharmaceuticals
Favipiravir	RdRp inhibitor	Ebola	Phase 3 NCT04373733 NCT04349241 NCT04529499 et al	Toyama Chemical
Remdesivir	RdRp inhibitor	Ebola	Phase 4 NCT04252664 NCT04257656 NCT04315948	Gilead
Molnupiravir	RdRp inhibitor	Influenza	Obtain FDA EUA	Merck
VV116	RdRp inhibitor		Phase 3 NCT05341609 NCT05242042 NCT05279235	Chinese scientific research team
Penciclovir		Influenza	Preclinical	Novartis
Nitazoxanide	Interferon response	Antiparasitic	Phase 3 NCT04486313 NCT05157269	Romark Laboratories
Azvudine	Interferon response	HIV	Phase 3 NCT04668235 NCT05033145	Zhengzhou University team
Nafamostat	TMPRSS2 inhibitor	Acute kidney injury	Phase 2 NCT04352400 NCT04390594	Shan Chemical Factory
Camostat mesilate	TMPRSS2 inhibitor	Chronic pancreatitis	Phase 3 NCT04657497
Chloroquine / Hydroxychloroquine	Interference with transport and fusion of viruses	Malaria	Several clinical trials ChiCTR2000029609/ NCT04315948 ChiCTR2000029868 ChiCTR2000029803 et al	Bayer
Arbidol	Blocking virus entry by interfering with clathrin	Influenza	Phase 4 NCT04252885 NCT04260594	Moscow-based Masterlek
Apilimod	Lipid kinase inhibitor		Phase 2 NCT04446377
Carrimycin	Blocking virus entry	Mycobacterium tuberculosis	Phase 3 NCT04672564	Chinese Academy of Medical Sciences team
Tetrandrine	Two‐pore channel 2 inhibitor	Sillicosis	Phase 4 NCT04308317
Cepharanthine	Reverse most dysregulated genes and pathways in infected cells	Leukopenia	Phase 2 NCT05398705
E-64d (Aloxistatin)	Cat B/L inhibitor		Preclinical
Lopinavir/Ritonavir	M^pro inhibitor	HIV	Phase 3 NCT04321174 NCT04364022	Abbvie
Boceprevir	M^pro inhibitor	HCV	Preclinical
Suramin	M^pro inhibitor	Antiparasitic	Preclinical
Ebselen	M^pro inhibitor	HIV	Preclinical
GRL-0617	PL^pro inhibitor	SARS-CoV	Preclinical	Peking University team
Carmofur	M^pro inhibitor	Antineoplastic	Preclinical
Calpeptin	M^pro inhibitor	Calpain inhibitor	Preclinical
Pelitinib	M^pro inhibitor	Non-small-cell lung cancer	Preclinical	Wyeth
Darunavir	M^pro inhibitor	HIV	Preclinical	Tibotec
Sabizabulin		Prostatic cancer	Phase 3 NCT04842747	Veru
Proxalutamide	AR inhibitor	Prostatic cancer	Phase 3 NCT04728802 NCT04853134 NCT04870606 et al	Kintor
HC-1119	AR inhibitor	Prostatic cancer	Phase 3 NCT04986176	Hinova

Inhibitor	Reported mechanism of action	Testing model	Activity IC₅₀/EC₅₀/μmol·L^-1	Toxicity CC₅₀/μmol·L^-1	Clinical information	Ref.
11a (DC402234/FB2001)	M^pro	In vitro	0.053	> 100	Phase 1 NCT05197179 NCT04766931	[93]
11b	M^pro	In vitro	0.040	> 100	Preclinical	[93]
MI-09	M^pro	In vitro	0.86	> 500	Preclinical	[94]
MI-30	M^pro	In vitro	0.54	> 500	Preclinical	[94]
13b	M^pro	In vitro	0.67		Preclinical	[95]
N3	M^pro	In vitro	16.77		Preclinical	[81]
PF-07321332	M^pro	In vitro	0.21	> 50	Paxlovid obtain FDA EUA	[96]
S-217622	M^pro	In vitro	0.29		Phase 3 NCT05305547	[98]
PBI-0451	M^pro				Phase 1 NCT05011812
EDP-235	M^pro				Phase 1 NCT05246878
SIM0417 (SSD8432)	M^pro				Phase 1 NCT05339646
BE-33	E	In vitro	0.94	31.46	Preclinical	[97]
RAY003					Preclinical

Inhibitor	Reported mechanism of action	Testing model	Activity IC₅₀/EC₅₀/μmol·L^-1	Toxicity CC₅₀/μmol·L^-1	Clinical information	Ref.
11a (DC402234/FB2001)	M^pro	In vitro	0.053	> 100	Phase 1 NCT05197179 NCT04766931	[93]
11b	M^pro	In vitro	0.040	> 100	Preclinical	[93]
MI-09	M^pro	In vitro	0.86	> 500	Preclinical	[94]
MI-30	M^pro	In vitro	0.54	> 500	Preclinical	[94]
13b	M^pro	In vitro	0.67		Preclinical	[95]
N3	M^pro	In vitro	16.77		Preclinical	[81]
PF-07321332	M^pro	In vitro	0.21	> 50	Paxlovid obtain FDA EUA	[96]
S-217622	M^pro	In vitro	0.29		Phase 3 NCT05305547	[98]
PBI-0451	M^pro				Phase 1 NCT05011812
EDP-235	M^pro				Phase 1 NCT05246878
SIM0417 (SSD8432)	M^pro				Phase 1 NCT05339646
BE-33	E	In vitro	0.94	31.46	Preclinical	[97]
RAY003					Preclinical

Peptide	Sequence	Tesing mode	IC₅₀/EC₅₀ /μmol·L^-1	CC₅₀ /μmol·L^-1	Ref.
EK1	SLDQINVTFLDLEYEMKKLEEAIKKLEESYIDLKEL	In vitro	2.468		[120]
EK1C4	EK1-GSGSG-PEG4-Chol	In vitro	0.036 5		[120]
EKL1C	NVTFLDLEYEMKKLEEAIKKLEESYIDLKELGTYEY-GSG-C(Chol)	In vitro	0.045	10	[121]
N-0385	Ms-Gln-Phe-Arg-kbt	In vitro	2.3	3 470	[123]
2019-nCoV-HR2P	DISGINASVVNIQKEIDRLNEVAKNLNESLIDLQEL	Pseudovirus	0.18		[118]
[SARS_HRC-PEG₄]₂-Chol	[DISGINASVVNIQKEIDRLNEVAKNLNESLIDLQEL-PEG₄]₂-Chol	In vitro	~0.3	> 100	[122]

Peptide	Sequence	Tesing mode	IC₅₀/EC₅₀ /μmol·L^-1	CC₅₀ /μmol·L^-1	Ref.
EK1	SLDQINVTFLDLEYEMKKLEEAIKKLEESYIDLKEL	In vitro	2.468		[120]
EK1C4	EK1-GSGSG-PEG4-Chol	In vitro	0.036 5		[120]
EKL1C	NVTFLDLEYEMKKLEEAIKKLEESYIDLKELGTYEY-GSG-C(Chol)	In vitro	0.045	10	[121]
N-0385	Ms-Gln-Phe-Arg-kbt	In vitro	2.3	3 470	[123]
2019-nCoV-HR2P	DISGINASVVNIQKEIDRLNEVAKNLNESLIDLQEL	Pseudovirus	0.18		[118]
[SARS_HRC-PEG₄]₂-Chol	[DISGINASVVNIQKEIDRLNEVAKNLNESLIDLQEL-PEG₄]₂-Chol	In vitro	~0.3	> 100	[122]

抗COVID-19药物的研究进展

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林梨萍 ¹ , 唐飞 ¹^,² , 许瑞安 ¹ , 崔秀灵 ¹^,^*

药学学报 | 综述 2023,58(1): 39-51

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药学学报 |综述 2023 , 58 (1) : 39 -51

抗COVID-19药物的研究进展

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林梨萍¹, 唐飞¹^,², 许瑞安¹, 崔秀灵¹^,^*

作者信息

1.华侨大学生物医学学院, 分子药物教育部工程研究中心, 福建省分子医学重点实验室, 福建省高校精准医学与分子诊断重点实验室, 厦门市海洋与基因药物重点实验室, 福建厦门 361021

2.厦门市疾病预防控制中心, 福建厦门 361021

通讯作者:

*崔秀灵, Tel: 86-592-6162996, E-mail: cuixl@hqu.edu.cn

Progress of the development of anti-COVID-19 drugs

Li-ping LIN¹, Fei TANG¹^,², Rui-an XU¹, Xiu-ling CUI¹^,^*

Affiliations

1. Engineering Research Center of the Ministry of Education for Molecular Drugs, Fujian Key Laboratory of Molecular Medicine, Fujian Key Laboratory of Precision Medicine and Molecular Diagnosis, Xiamen Key Laboratory of Marine and Genetic Drugs, College of Biomedicine, Huaqiao University, Xiamen 361021, China

2. Xiamen Center for Disease Control and Prevention, Xiamen 361021, China

出版时间: 2023-01-12 doi: 10.16438/j.0513-4870.2022-0707

文章导航

摘要

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自2019年末SARS-CoV-2病毒引起的新冠疫情COVID-19 (也称为2019-nCoV) 暴发以来, 快速传播, 席卷全球。除了研发有效疫苗, 迫切需要寻找安全有效的抗新冠病毒药物来对抗这种疾病。FDA紧急授权的paxlovid、molnupiravir、sotrovimab和bebtelovimab被证明对Omicron有效。本文综述了3年来全球对该病毒有效的抑制剂, 包含受体抑制剂、抗体、天然产物抑制剂、合成抑制剂及临床上对其他RNA病毒有效的广谱抗病毒药物的研发进展。

关键词

新型冠状病毒肺炎 / 靶标 / 药物治疗 / 老药新用 / 新药研发

Abstract

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Since the outbreak of the novel coronavirus (SARS-CoV-2) disease COVID-19 (also known as 2019-nCoV) caused by SARS-CoV-2 in the end of 2019, it has spread rapidly in worldwide. Besides developing effective vaccines, it is urgent to develop safe and effective anti-SARS-CoV-2 drugs to fight this disease. Paxlovid, molnupiravir, sotrovimab and bebtelovimab are urgently authorized by FDA have been proved to be effective against Omicron. This manuscript mainly reviews the recent progress of effective inhibitors against the virus in the world, including receptor inhibitors, antibodies, natural product inhibitors, synthetic inhibitors and broad-spectrum antiviral drugs that are effective against other RNA viruses.

Key words

COVID-19 / target / medication / drug repurposing / drug discovery

引用本文

林梨萍, 唐飞, 许瑞安, 崔秀灵. 抗COVID-19药物的研究进展. 药学学报, 2023 , 58 (1) : 39 -51 . DOI: 10.16438/j.0513-4870.2022-0707

Li-ping LIN, Fei TANG, Rui-an XU, Xiu-ling CUI. Progress of the development of anti-COVID-19 drugs[J]. Acta Pharmaceutica Sinica, 2023 , 58 (1) : 39 -51 . DOI: 10.16438/j.0513-4870.2022-0707

正文

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2019年末, 一种高致病性人类冠状病毒席卷全球。该病原体被鉴定为一种新型的包膜RNA β冠状病毒, 国际病毒学分类委员会的冠状病毒科研究组将其命名为严重急性呼吸系统综合征冠状病毒2 (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2), 世界卫生组织(World Health Organization, WHO) 将该病毒引起的疾病命名为COVID-19 (前期也称为2019-nCoV)^[1-6]。新型冠状病毒SARS-CoV-2是目前人类已知的第七种冠状病毒。由于这种病毒的高发病率和死亡率, 根据WHO官网报道截止至2022年6月23日, 全球范围内COVID-19患者累计确诊病例超过5.39亿, 累计死亡人数高达632万。

2021年3月新冠病毒的双突变体, Delta SARS-CoV-2 (B1.617) 变异株的出现加剧了疫情, 激发了第二波新冠大流行。D164G突变增强了新冠病毒进入宿主细胞和复制的能力, 使得该突变毒株更活跃、更强大、传播速度更迅猛^{[7, 8]}。疫苗和抗病毒药物历来是用来控制、预防和治疗危及生命的病毒性疾病的常规方法。针对SARS-CoV-2感染, 国内外先后研制出各种疫苗广泛接种, 根据WHO官网报道截止至2022年6月20日疫苗接种已达11 912 594 538剂。然而COVID-19疫情是人类自大流感出现以来, 全球最大的流行病危机。迄今研发的疫苗和单克隆抗体仅仅对COVID-19部分有效^{[9, 10]}, 免疫力下降和疫苗逃逸突变体不断出现。目前Omicron SARS-CoV-2 (B.1.1.529) 变种导致新冠病患激增突显了这一点^[11]。三年多来新冠特效药的缺失和现有疫苗局限性致使全球疫情起伏不定, 对人类健康与生存造成巨大威胁, 并给全球经济复苏造成毁灭性打击。加之, 全球迄今仍缺乏针对COVID-19标准的治疗方法^[12], 形势严峻, 迫切需要开发能作为治疗COVID-19的抗新冠病毒SARS-CoV-2特效药。

新冠疫情暴发后, 针对COVID-19的治疗, 目前世界上思路主要有两种: 在人们确定新冠病毒SARS-CoV-2的病毒结构的基础上, 寻找治疗COVID-19药物靶标, 进而探索“老药新用”的可行性和新药研发。

1 抗COVID-19药物靶标

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三年来, 全球科学家研究发现该病毒共有5个主要的蛋白区域和功能, 分别是在5′末端由开放阅读框1a/b编码的16个非结构蛋白(nonstructural proteins, nsp) 和由3′末端编码的刺突蛋白S (spike, S蛋白)、膜蛋白(membrane, M蛋白)、外壳蛋白(envelope, E蛋白)和核衣壳蛋白(nucleocapsid, N蛋白)^{[13, 14]}。

新冠病毒基因组编码非结构蛋白, 例如冠状病毒主要蛋白酶(main protease, M^pro, 也称为3C-like protease, 3CL^pro)、木瓜样蛋白酶样蛋白酶(papain-like protease, PL^pro)、解旋酶(helicase) 和RNA依赖的RNA聚合酶(RNA-dependent RNA polymerase, RdRP)^[15]。上述4种非结构蛋白是病毒生命周期的关键酶, 而结构蛋白(S蛋白) 在病毒进入过程中参与病毒-细胞受体相互作用, 这5种蛋白质是开发COVID-19治疗药物的主要靶标^[16-18]。

2 COVID-19药物治疗

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鉴于SARS-CoV-2不断在突变, 目前尚无针对这种新病毒的特异性疫苗防护手段。因此, 需要从新冠病毒结构特性, 寻找到有效的临床治疗药物来对抗这一疾病。目前全球生物医学研究人员从不同的角度进行探索, 主要研发进展如下:

2.1 抗体

冠状病毒感染导致单核细胞、巨噬细胞和树突细胞活化并分泌白介素-6 (interleukin-6, IL-6) 等促炎性细胞因子, 引发细胞因子风暴, 因此干扰IL-6分泌可能是COVID-19的潜在疗法^[19-21]。托珠单抗(tocilizumab) 可以特异性结合IL-6受体和可溶性IL-6受体来抑制促炎信号的转导。临床研究发现托珠单抗可以降低死亡率并改善临床结果, 然而这些试验也受到异质人群的影响, 托珠单抗能否应用于重症COVID-19患者尚未得出结论^[22]。

中和抗体(neutralizing antibodies, nAb) 也是抗病毒药物研发的一个方向。针对COVID-19大流行, S1亚基的N端结构域、受体结合结构域(receptor-binding domain, RBD) 和S2亚基可用作开发nAb的靶标, 利用RBD蛋白筛选出抗SARS-CoV-2的nAb是一种非常有效的方法^[23]。在体外实验中血浆疗法显示出良好的活性, 但是在多项临床试验中, 血浆疗法均未显示出对新冠肺炎患者的临床益处, 恢复期血浆是否会使其他患者群体受益尚不清楚, 需要在其他充分有力的随机临床试验中进行评估^[24-28]。

新冠疫情暴发以来, 大量抗体进入临床试验。中和抗体bamlanivimab (LY3819253/LY-CoV555) 在动物体内具有抗病毒活性, 原理是以高亲和力结合病毒S蛋白的RBD并阻止病毒与血管紧张素转移酶II (angiotensin-converting enzyme II, ACE2) 受体的相互作用^[29]。在临床试验中bamlanivimab基线症状改善幅度大于安慰剂, 联合使用bamlanivimab和etesevimab (LY-CoV016) 减少了与COVID-19相关的住院率和死亡率^[30-32]。靶向SARS-CoV-2 S蛋白RBD的单克隆抗体casirivimab和imdevimab组合疗法(称为REGEN-CoV) 在临床试验中能够降低基线血清阴性的住院患者28天死亡率, 缩短了症状性疾病和高病毒载量的持续时间^[33-35]。目前etesevimab、REGEN-COV、bamlanivimab这3种nAb已获得美国食品药品管理局(Food and Drug Administration, FDA) 紧急使用授权(emergency use authorization, EUA) 许可, 其有效性还需要临床的检验。

SARS-CoV-2的S蛋白上的位点突变较快, 之前针对不同变异株研发出来的抗体对新的变异株活性可能减弱或者失效。Planas等^[36]将针对Delta毒株研发的9种抗体用于新变异的Omicron毒株的治疗, 只有sotrovimab被证明有效, 其作用机制是通过与S蛋白结合以插入融合蛋白并将病毒RNA注入细胞阻止病毒随后的活性, 获得FDA EUA许可。此前获得FDA EUA许可的bamlanivimab、etesevimab和REGEN-CoV在此次研究中被证实对Omicron失去中和活性, cilgavimab和tixagevimab组合(称为Evusheld) 对Omicron的中和活性也减弱了。Iketani等^[37]对19种单克隆抗体进行实验, 发现只有LY-CoV1404 (bebtelovimab) 可以中和Omicron毒株变体的全部亚型, 于2022年2月12日获得FDA EUA许可, 而sotrovimab对Omicron变体BA.2的活性与变体BA.1相比减弱了27倍。

由于缺乏大规模的临床证据, 仍然需要探索单克隆抗体对变异体的疗效。同时, 因为病毒的不断突变, 还需要对病毒突变体进行持续的监测。

2.2 受体抑制剂

SARS-CoV-2 S蛋白与宿主细胞上的受体ACE2结合, 介导病毒通过内吞作用进入靶细胞, 因此可以用抗体或小分子靶向SARS-CoV-2和ACE2相互作用的位点以阻断ACE2受体^[38-41]。研究发现过量可溶性ACE2和人重组可溶性ACE2可以阻断SARS-CoV-2感染的路径, 保护肺免受损伤^{[42, 43]}。此外, 基于野生型ACE2设计的三聚体ACE2蛋白T-ACE2以极高的亲和力与SARS-CoV-2结合并抑制SARS-CoV-2感染^[44]。在重症患者中使用人ACE2中和抗体, 血浆和呼吸系统中显示对病毒高清除率^[45], 但其半衰期短, 而修饰过的ACE2-Fc受体融合蛋白HLX71可以改善药代动力学^[46], 刘俊丽等^[47]发现HLX71在动物体内具有抗新冠病毒活性, HLX71和HLX70 nAb混合物在抗病毒活性方面具有协同作用, 并覆盖更广泛的RBD变体。目前HLX71已完成临床I期试验, 数据尚未公布。ACE2作为SARS-CoV-2的进入受体为感染初期的治疗开发提供了关键靶标, HLX71是否可以成为治疗COVID-19的药物, 有待进一步的实验验证。

2.3 探索老药新用

新药研发周期长, 风险高, 面对突如其来的疫情, 从临床使用的药物中筛选出具有抗新冠病毒活性药物, 可极大地缩短研发时间和成本。老药新用中筛选出的31种化合物化学结构见图 1, 研究进展见表 1。

中国科学院武汉病毒研究所等国内外研究团队率先对已知抗病毒药物进行了活性筛选, 发现了利巴韦林(ribavirin)、喷昔洛韦(penciclovir)、瑞德西韦(remdesivir)、法匹拉韦(favipiravir)、硝唑尼特(nitazoxanide)、萘莫司他(nafamostat) 和氯喹(chloroquine) 这7个药物在细胞水平对新冠病毒有明显的抑制作用。这是全球最早报道的在细胞中具有抗新冠病毒活性的老药^[48]。其中, 瑞德西韦和氯喹的活性最好, 引发公众的关注。

SARS-CoV-2的RdRp由nsp7、nsp8和nsp12组成, nsp12中发现新鉴定的β-发夹结构域且同时存在高度保守的残基、定位模板和引物以对进入核苷酸进行在线攻击^[49-51]。瑞德西韦作用机制是在体内三磷酸化后, 可与RdRp竞争性结合, 整合至新生RNA链中, 从而阻断病毒复制^[52]。在疫情初期, 瑞德西韦在治疗中可以加快患者痊愈而引发关注, 被称为“人民的希望”。然而在2020年4月柳叶刀上报道瑞德西韦并不能显著加快患者的恢复速度和病毒清除率, 也不能有效降低死亡率^[53]。2020年10月新英格兰医学杂志上报道瑞德西韦在治疗第15天时临床效果显著, 可以缩短康复时间^[54]。2020年10月22日, FDA率先批准其作为治疗新冠病毒感染的首款EUA药物, 然而其仅局限于对早期感染有效, WHO并不推荐其用于临床治疗。瑞德西韦作为核苷类似物, 耐药性是该类药物共有的缺点, Gandhi等^[55]在免疫力低下的新冠病毒感染患者中使用瑞德西韦后发现nsp12 E802D耐药突变体, 耐药变异的传播会增加原发性耐药性的风险。

瑞德西韦的口服衍生物VV116在细胞和动物水平上对SARS-CoV-2有显著的抑制活性, 通过其核苷三磷酸形式靶向病毒RdRp发挥作用, I期临床试验显示其具有良好的口服生物利用度^{[56, 57]}。VV116的临床结果显示在Omicron首次确诊阳性患者5天内给药, 核酸转阴时间从11.13天缩短至8.56天, 在病毒感染早期表现出良好的治疗效果^[58]。目前VV116正在III期临床试验中。与瑞德西韦类似, 核苷酸类似物药物利巴韦林和法匹拉韦通过模拟RNA核苷酸并与复制的RNA共价连接来抑制病毒RNA的转录。一项临床研究表明对轻、中度新冠肺炎患者, 早期三联合使用利巴韦林、干扰素β-1b和洛匹那韦(lopinavir)/利托那韦(ritonavir) 抗病毒治疗在缓解症状、促进病毒脱落和缩短住院时间方面安全性优于单独使用洛匹那韦/利托那韦^[59]。在确诊的COVID-19患者中, 法匹拉韦组的病毒清除中位时间较短, 且胸部CT也有改善, 法匹拉韦在疾病进展和病毒清除方面对COVID-19表现出很好的治疗反应^[60]。由于临床试验规模较小, 法匹拉韦在COVID-19的有效性仍然存在争议, 需要进一步临床试验证据支撑。

氯喹作为治疗和预防疟疾的药物已有70多年的历史, 最早期的报道显示, 氯喹在细胞水平上, 针对新冠病毒复制的半数效应浓度EC₅₀达1.13 μmol·L^{-1 [48]}, 但其临床毒性大, 而将氯喹与curcurbit[7]uril制成的超分子抑制剂可以降低氯喹的非特异性毒性并提高抗冠状病毒活性, 具有成为抗冠状病毒药物的潜力^[61]。同时, 作为氯喹衍生物的羟氯喹(hydroxychloroquine) 也受到广泛关注, 其安全性和耐受性均优于氯喹。无奈动物实验结果否定了氯喹和羟氯喹对新冠感染的治疗作用^{[62, 63]}, 临床试验同样表明其未能明显减轻临床症状^{[64, 65]}。目前, 氯喹和羟氯喹治疗新冠肺炎是否有效尚存争议, 有待于进一步研究。

常俊标团队发明了国内首创的拥有自主知识产权的抗艾滋病毒口服药物——阿兹夫定(azvudine, FNC), 2021年7月20日, 获注册批准上市, 用于治疗高病毒载量的成年艾滋病患者。2020年4月, 该团队将FNC进行COVID-19测试, 体内、体外活性试验均表明FNC对新型冠状病毒具有明确的抗病毒活性^[66]。FNC的III期临床试验已结束, 结果显示其在治疗新冠轻重症方面都非常有效, 其临床数据尚待公布。

曾作为治疗流感的广谱抗病毒药物阿比朵尔(arbidol), 通过靶向抑制病毒-宿主细胞的融合防止病毒进入流感病毒的宿主细胞中^[67]。研究发现其不仅可以有效阻止SARS-CoV-2病毒附着, 而且还阻止病毒从细胞内囊泡释放从而阻止病毒进入^[68]。临床试验显示, 较洛匹那韦/利托那韦组相比, 阿比朵尔组患者阴性转化率显著升高, 有助于临床和实验室改善, 阿比朵尔单药治疗COVID-19效果比洛匹那韦/利托那韦更有效^{[69, 70]}。一项临床试验显示阿比朵尔和洛匹那韦/利托那韦联用, 会提高病毒清除率和胸部CT扫描^[71]。

蛋白酶对S蛋白的激活是冠状病毒进入的重要步骤^[72]。Hoffmann等^[39]研究发现SARS-CoV-2利用细胞跨膜丝氨酸蛋白酶(transmembrane protease serines, TMPRSS2) 和内体半胱氨酸蛋白酶组织蛋白酶B和L (cathepsin B/L, Cat B/L) 来激活S蛋白, TMPRSS2抑制剂卡莫司他甲磺酸盐(camostat mesilate) 和Cat B/L抑制剂E-64d都可以部分抑制SARS-CoV-2 S驱动的细胞进入^[39]。卡莫司他甲磺酸盐II期临床试验结果显示, 与安慰剂组相比, 4天时卡莫司他磺酸盐与鼻咽SARS-CoV-2病毒载量减少无关, 但该药物能够改善味觉和嗅觉丧失的情况, 目前正在推进III期临床试验^[73]。

EIDD-2801 (又名molnupiravir) 是靶向RdRp的口服核苷类似物, 对各种RNA病毒具有广谱的抗病毒活性, 通过在病毒复制中将突变引入病毒基因组导致“错误灾难”和病毒死亡来发挥其抗病毒作用, 其对多种冠状病毒的有效性和口服生物利用度凸显了其作为有效抗SARS-CoV-2的潜在用途^[74]。Molnupiravir在COVID-19的III期临床中对新冠病毒变种有效, 可以降低一半重症率, 成为获得FDA EUA的第二种治疗COVID-19口服药。该药物可能会影响骨骼和软骨的生长, 美国FDA未授权用于年龄低于18岁患者的治疗, 而且该药物对孕妇胎儿存在安全问题。由于其会导致病毒RNA合成错误, 部分人也担心它可能会加速这种病毒的进化^[75]。李鹏飞等^[76]在细胞中研究表明molnupiravir有效抑制Omicron突变体的感染, 然而之后临床数据显示molnupiravir的药效不如预期, 法国政府于2021年12月22日宣布取消先前订购的5万剂molnupiravir订单, 成为首个公开取消这款口服药订单的国家。

靶向SARS-CoV PL^pro设计的GRL-0617在抑制SARS-CoV-2 PL^pro方面非常有效, 削弱病毒诱导的细胞致病作用, 维持抗病毒干扰素途径并减少感染细胞中的病毒复制^{[77, 78]}。前列腺癌靶向药sabizabulin、普克鲁胺(proxalutamide) 和HC-1119也进入新冠临床III期试验。Sabizabulin在重症住院患者中效果显著, 已向FDA提交EUA申请。

通过药物筛选, 化合物依布硒(ebselen)、卡莫氟(carmofur)、calpeptin、pelitinib、苏拉明(suramin)、boceprevir和达芦那韦(darunavir) 都对SARS-CoV-2 M^pro显示出良好的抑制活性^[79-86]。童贻刚课题组^{[87, 88]}在SARS-CoV-2高度同源病毒株xCoV中筛选发现千金藤素(cepharanthine) 在10 μmol·L^-1的剂量下对xCoV病毒复制的抑制效果为阴性对照组的15 393倍, 通过逆转感染细胞中大多数失调的基因和途径, 来发挥抗冠状病毒感染效果。千金藤素药作为一个临床上使用的药物, 仍需要在动物模型和人体试验得到应有的验证。

我国首个利用合成生物学技术自主研发的抗感染新药可利霉素(carrimycin) 和PIKfyve激酶抑制剂apilimod在进入过程中能抑制病毒复制发挥抗病毒效果^{[89, 90]}。汉防己甲素(tetrandrine) 与瑞德西韦联用在细胞水平对新冠病毒表现出显著的协同作用, 汉防己甲素对矽肺的治疗有明确的肺部药理活性, 其对新冠病毒的疗效还需在小鼠体内进行药效学研究^[90-92]。

2.4 合成抑制剂

新冠疫情暴发后, 饶子和/杨海涛团队^[81]快速表达了COVID-19 M^pro并获得了高分辨率晶体结构, 为该研究提供了理论基础。

中国科学院上海药物研究所和上海科技大学联合抗疫攻关团队采用计算机辅助药物设计与药物化学结构优化策略, 以醛基作为反应弹头, 设计并合成了一系列拟肽醛类化合物。经过细胞模型筛选, 化合物N3对SARS-CoV-2 M^pro显示出中等的抑制效果, 化合物11a和11b具有较强的抑制作用, 目前11a完成了临床前评价研究, 已向中国食品与药品监督管理局和美国的FDA提交了临床申请注册申报, 并获得了FDA的临床试验批准^{[81, 93]}。随后杨胜勇团队跟进对该类拟肽醛化合物进行结构改造, 并开展转基因小鼠动物探索^[94]。

Hilgenfeld科研团队通过对SARS-CoV M^pro设计的α-酮酰胺抑制剂化合物进行结构修饰得到的化合物13b能够显著抑制SARS-CoV-2且可以单独与SARS-CoV-2的M^pro晶体结构结合, 药代动力学显示出明显的肺向性, 适合通过吸入途径给药^[95]。

口服药物具有给药方式简便、可及性好、适合大范围使用等优点。辉瑞的PF-07321332是以氰基作为反应弹头, 靶向SARS-CoV-2 M^pro, 对Alpha、Beta、Gamma和Delta这四种变体都表现出了等效的抗病毒活性, 同时保护小鼠免受Beta和Delta变体的鼻内感染^[96]。辉瑞将PF-07321332和利托那韦组合的一款口服药物Paxlovid, 由于其临床II期和III期效果显著, 获得FDA EUA许可的第一款抗COVID-19的口服药物, 同时该药物于2022年2月在中国批准上市, 用于新冠病毒的临床治疗。辉瑞公布的Paxlovid临床试验数据显示, 在预防重症高风险患者住院和死亡方面, 该药物的有效性为89%, 对Omicron毒株也有效, 但其不良反应包括味觉受损、腹泻、高血压和肌肉疼痛等, 并且不能用于严重肾或肝功能损害者。其他的靶向SARS-CoV-2 M^pro的口服药物S-217622正在推进临床III期, PBI-0451和EDP-235这两个口服药物也正在推进临床I期试验。SIM0417临床I期试验已完成, RAY003尚处在临床前研究阶段。

SARS-CoV-2 E蛋白可形成一种阳离子通道, 该通道的异源表达可导致宿主细胞死亡, 通过结构设计合成了通道抑制剂BE-33对SARS-CoV-2感染表现出卓越的抗病毒活性, 该活性与抑制E通道呈正相关, E蛋白是一种很有希望的抗SARS-CoV-2的药物靶点^[97]。

以上基于SARS-CoV-2蛋白设计的化合物结构归纳于图 2 (部分化合物结构未公开), 研究信息见表 2^{[81, 93-98]}。

2.5 天然产物抑制剂

海洋天然产物具有类似的药物特性和很高的生物利用度, 可以有效抵抗病毒性疾病。天然产物抑制剂的化学结构见图 3。Khan等^[99]发现5个海洋天然产物都能够停靠在SARS-CoV-2 M^pro的晶体结构中, 其中C-1与活性位点和周围残基相互作用形成许多氢键和疏水相互作用是用作抗SARS-CoV-2的潜在抑制剂。Gentile等^[100]利用计算机技术在14 064个分子的海洋天然产物库中筛选出17种潜在的SARS-CoV-2 M^pro抑制剂。

天然产物库活性筛选发现白果新酸(ginkgolic acid)、大麻酰胺A (cannabisin A)、异麦角甾苷(isoacteoside) 以及黄酮类化合物黄芩甙(baicalin)、草质素(herbacetin) 和大蓟苷(pectolinarin) 都对SARS-CoV-2 M^pro有显著的抑制活性^{[82, 101, 102]}。原花青素(proanthocyanidins) 在体外减弱SARS-CoV-2复制, 其作用机制是将原花青素插入E蛋白N末端前庭的孔中, 起到通道阻滞剂的作用^[103]。SARS-CoV-2感染可激活先天和适应性免疫反应, 肿瘤坏死因子(TNF) 和IL-6是细胞因子风暴加重COVID-19患者病情的主要原因^[104]。

据国内相关文献报道由13种草药组成的中成药连花清瘟(LH) 可以通过抑制病毒传播和免疫调节达到广谱抗病毒效果。在体外实验中LH能显著抑制SARS-CoV-2病毒复制、改变病毒形态并干预4种与肺炎相关的细胞因子的表达, 表明LH可能与SARS-CoV-2诱导的细胞因子风暴有关^{[105, 106]}。LH中的多种成分对ACE2有较高的抑制作用, 为治疗COVID-19提供化学和生化证据^[107]。多项开放性实验中都表明LH显著改善COVID-19的临床症状^{[105, 108, 109]}。LH的临床研究为COVID-19的中医治疗提供了理论参考, 但是因为其未进行随机+双盲实验, 有效性也受到了外界质疑。

蒲地蓝消炎口服液是由蒲公英、板蓝根、苦地丁、黄芩这4种中药制剂为主要原料, 具有抗病毒和抗菌作用, 其在体外和体内均表现出较强的抗SARS-CoV-2活性和较好的疗效, 减轻肺的病理损伤并减少血清中的促炎细胞因子IL-10和TNF-α的产生, 可用于临床治疗SARS-CoV-2感染引起的肺炎或与其他有效抗病毒药物联用^[110]。甘草根的提取物甘草酸(glycyrrhizic acid) 有抗炎功效, 具有成为减轻COVID-19重症患者的细胞因子风暴和炎症反应的潜在药物^[111]。在COVID-19的临床治疗中, 中西药结合有助于缓解症状, 药理研究表明中药有效性可能是通过对宿主的调控和某些抗病毒作用^{[112, 113]}。

姜黄素(curcumin) 可以影响SARS-CoV-2的复制周期, 对D614G毒株和Delta毒株具有抗病毒作用和免疫调节特性^[114]。临床研究显示姜黄素可以改善氧合作用并缩短住院时间, 加快急性炎症期恢复过程^{[115, 116]}。因为姜黄素临床试验样本量较少, 还需要在更大的样本量中进行随机对照试验。

此外, 人们也扩大探索的视野, 把眼光投向天然海洋小分子和大分子化合物^[117], 已发现多个具有抗新冠病毒小分子化合物, 可作为一条新药研发探索途径。

2.6 多肽类抑制剂

SARS-CoV-2 S蛋白受体的参与是S蛋白介导的病毒融合和进入的必要条件, 其中S2亚基中七肽重复序列1 (heptad repeat region 1, HR1) 和HR2区域在介导SARS-CoV-2与宿主细胞融合和进入宿主细胞中起关键作用, 使其成为药物设计的重要靶标之一^[118]。

靶向病毒S蛋白HR1保守位点的广谱冠状病毒融合抑制剂EK1肽和靶向HR2保守位点的脂肽2019-nCoV-HR2P对SARS-CoV-2均表现出强烈的膜融合抑制活性^[119]。带胆固醇修饰的脂肽EK1C4对SARS-CoV-2活性比EK1高67倍, 对耐药性有很高的遗传屏障, 然而该肽中的聚乙二醇(PEG) 接头可能会降低稳定性, 该项目组将EK1 HR2-CF中的PEG接头替换为氨基酸, 得到对蛋白水解酶的抵抗力明显更强的脂肽EKL1C, 同时显示出最有效的抗SARS-CoV-2活性, IC₅₀在纳摩尔水平^{[120, 121]}。De Vries等^[122]设计的脂肽[SARS_HRC-PEG₄]₂-Chol在雪貂内可以阻断宿主内SARS-CoV-2病毒复制, 鼻内预防性给药可以保护雪貂免受感染。该脂肽特别稳定, 可以很容易地转化为安全有效的鼻内预防药物。

Shapira等^[123]研究发现靶向TMPRSS2的多肽类小分子化合物N-0385可以阻止新冠病毒及其变异株的感染, 此化合物对TMPRSS2的抑制率可达83%, 效果远高于卡莫司他甲磺酸盐(53%), N-0385在动物模型中对小鼠的感染和死亡具有广泛的保护作用。

刘娜等^[124]利用GRL-0617与PL^pro特异性底物LRGG硫盐连接肽得到的新型肽-药物偶联物EC-M可以共价标记PL^pro活性位点C111, 为新型肽-药物偶联物设计提供有希望的机会。

以上6种肽类序列及研究信息归纳于表 3。

3 展望

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由于SARS-CoV-2病毒的高传播率、高发病率且缺乏有效的药物治疗造成了该疾病的大流行, 迫切需要找到有效药物来防治新冠病毒感染。临床上, 国际范围内通常使用的抗病毒药物, 分为直接抗病毒的药物和作用于宿主的药物^{[125, 126]}。前者包括核苷类似物、蛋白酶抑制剂等, 能直接作用于病毒的特定靶标; 后者包括干扰素、免疫调节剂等。迄今为止, 多种药物用于新冠肺炎临床治疗^{[125, 127]}, 然而能根除病毒的药物极少, 有的则用于疾病早期, 例如瑞德西韦是FDA批准的首款用于治疗新冠肺炎的药物, 但由于其局限性, 没有在美国以外的地方被广泛使用。

迄今研发的疫苗和单克隆抗体仅仅对COVID-19部分患者有效, 无法完全阻断SARS-CoV-2传播, 更为严峻的是世界范围内越来越多的新冠变体的出现, FDA共授予EUA的6种单克隆抗体中只有sotrovimab和bebtelovimab被证明对Omicron有效, 其中只有bebtelovimab可以中和Omicron突变株的全部亚型, 增加防治的难度^[37]。

考虑到口服给药的便携性, paxlvid和molnupiravir是率先获得FDA EUA许可的两款口服抗新冠药物。Paxlvid不可忽视的不良反应和受限的适用人群也在一定程度上限制了该类药物的使用。Molnupiravir是靶向RdRp的核苷类似物抑制剂, 核苷类药物前期固然有较高的选择性和较理想的RNA合成抑制效果, 但是美中不足的是难免出现类似广泛的核苷类和似物抗病毒药物, 随着给药时间的延长, 病毒的变异和耐药性等一直是挥之不去的难题。目前其他的口服药物如S-217622、PBI-0451、SIM0417和EDP-235还处在临床试验中。RAY003尚处在临床前研究阶段。

在全球疫情蔓延的情况下, 境外输入和本土传播增大了疫情防控的难度。基于长期抗病毒积累的历史经验和目前冠状病毒的超强变异性, 人类必须在与病毒抗争中不断地探索、力尽可能在不远的将来, 研发出长效的抗新冠特效药, 弥补目前新冠疫苗难以胜任的预防角色。

作者贡献: 该文章由林梨萍负责文献查阅及文章初稿撰写; 唐飞负责文献收集、整理与分析; 许瑞安和崔秀灵提出写作思路和指导、撰写与修改。

利益冲突: 所有作者均声明不存在利益冲突。

基金

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福建省创新药物与创新技术产业化(3502ZCQXT2021006)
泉州市抗新型冠状病毒感染肺炎药物筛选(2020SY003)
教育部111创新引智基地(BC2018061)

参考文献

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2023年第58卷第1期

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doi: 10.16438/j.0513-4870.2022-0707

接收时间：2022-06-09
首发时间：2025-11-21
出版时间：2023-01-12

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收稿日期：2022-06-09
修回日期：2022-07-08

基金

福建省创新药物与创新技术产业化(3502ZCQXT2021006)

泉州市抗新型冠状病毒感染肺炎药物筛选(2020SY003)

教育部111创新引智基地(BC2018061)

作者信息

2.厦门市疾病预防控制中心, 福建厦门 361021

通讯作者:

*崔秀灵, Tel: 86-592-6162996, E-mail: cuixl@hqu.edu.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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TxT

Drug	Reported mechanism of action	Original indication	Clinical information	Developer
Ribavirin	RdRp inhibitor	RSV/HCV	Phase 2 NCT04828564	ICN Pharmaceuticals
Favipiravir	RdRp inhibitor	Ebola	Phase 3 NCT04373733 NCT04349241 NCT04529499 et al	Toyama Chemical
Remdesivir	RdRp inhibitor	Ebola	Phase 4 NCT04252664 NCT04257656 NCT04315948	Gilead
Molnupiravir	RdRp inhibitor	Influenza	Obtain FDA EUA	Merck
VV116	RdRp inhibitor		Phase 3 NCT05341609 NCT05242042 NCT05279235	Chinese scientific research team
Penciclovir		Influenza	Preclinical	Novartis
Nitazoxanide	Interferon response	Antiparasitic	Phase 3 NCT04486313 NCT05157269	Romark Laboratories
Azvudine	Interferon response	HIV	Phase 3 NCT04668235 NCT05033145	Zhengzhou University team
Nafamostat	TMPRSS2 inhibitor	Acute kidney injury	Phase 2 NCT04352400 NCT04390594	Shan Chemical Factory
Camostat mesilate	TMPRSS2 inhibitor	Chronic pancreatitis	Phase 3 NCT04657497
Chloroquine / Hydroxychloroquine	Interference with transport and fusion of viruses	Malaria	Several clinical trials ChiCTR2000029609/ NCT04315948 ChiCTR2000029868 ChiCTR2000029803 et al	Bayer
Arbidol	Blocking virus entry by interfering with clathrin	Influenza	Phase 4 NCT04252885 NCT04260594	Moscow-based Masterlek
Apilimod	Lipid kinase inhibitor		Phase 2 NCT04446377
Carrimycin	Blocking virus entry	Mycobacterium tuberculosis	Phase 3 NCT04672564	Chinese Academy of Medical Sciences team
Tetrandrine	Two‐pore channel 2 inhibitor	Sillicosis	Phase 4 NCT04308317
Cepharanthine	Reverse most dysregulated genes and pathways in infected cells	Leukopenia	Phase 2 NCT05398705
E-64d (Aloxistatin)	Cat B/L inhibitor		Preclinical
Lopinavir/Ritonavir	M^pro inhibitor	HIV	Phase 3 NCT04321174 NCT04364022	Abbvie
Boceprevir	M^pro inhibitor	HCV	Preclinical
Suramin	M^pro inhibitor	Antiparasitic	Preclinical
Ebselen	M^pro inhibitor	HIV	Preclinical
GRL-0617	PL^pro inhibitor	SARS-CoV	Preclinical	Peking University team
Carmofur	M^pro inhibitor	Antineoplastic	Preclinical
Calpeptin	M^pro inhibitor	Calpain inhibitor	Preclinical
Pelitinib	M^pro inhibitor	Non-small-cell lung cancer	Preclinical	Wyeth
Darunavir	M^pro inhibitor	HIV	Preclinical	Tibotec
Sabizabulin		Prostatic cancer	Phase 3 NCT04842747	Veru
Proxalutamide	AR inhibitor	Prostatic cancer	Phase 3 NCT04728802 NCT04853134 NCT04870606 et al	Kintor
HC-1119	AR inhibitor	Prostatic cancer	Phase 3 NCT04986176	Hinova

Drug

Reported mechanism of action

Original indication

Clinical information

Developer

Ribavirin

RdRp inhibitor

RSV/HCV

Phase 2
NCT04828564

ICN Pharmaceuticals

Favipiravir

RdRp inhibitor

Ebola

Phase 3
NCT04373733
NCT04349241
NCT04529499 et al

Toyama Chemical

Remdesivir

RdRp inhibitor

Ebola

Phase 4
NCT04252664
NCT04257656
NCT04315948

Gilead

Molnupiravir

RdRp inhibitor

Influenza

Obtain FDA EUA

Merck

VV116

RdRp inhibitor

Phase 3
NCT05341609
NCT05242042
NCT05279235

Chinese scientific research team

Penciclovir

Influenza

Preclinical

Novartis

Nitazoxanide

Interferon response

Antiparasitic

Phase 3
NCT04486313
NCT05157269

Romark Laboratories

Azvudine

Interferon response

HIV

Phase 3
NCT04668235
NCT05033145

Zhengzhou University team

Nafamostat

TMPRSS2 inhibitor

Acute kidney injury

Phase 2
NCT04352400
NCT04390594

Shan Chemical Factory

Camostat mesilate

TMPRSS2 inhibitor

Chronic pancreatitis

Phase 3
NCT04657497

Chloroquine / Hydroxychloroquine

Interference with transport and fusion of viruses

Malaria

Several clinical trials
ChiCTR2000029609/
NCT04315948
ChiCTR2000029868
ChiCTR2000029803 et al

Bayer

Arbidol

Blocking virus entry by interfering with clathrin

Influenza

Phase 4
NCT04252885
NCT04260594

Moscow-based Masterlek

Apilimod

Lipid kinase inhibitor

Phase 2
NCT04446377

Carrimycin

Blocking virus entry

Mycobacterium tuberculosis

Phase 3
NCT04672564

Chinese Academy of Medical Sciences team

Tetrandrine

Two‐pore channel 2 inhibitor

Sillicosis

Phase 4
NCT04308317

Cepharanthine

Reverse most dysregulated genes and pathways in infected cells

Leukopenia

Phase 2
NCT05398705

E-64d (Aloxistatin)

Cat B/L inhibitor

Preclinical

Lopinavir/Ritonavir

M^pro inhibitor

HIV

Phase 3
NCT04321174
NCT04364022

Abbvie

Boceprevir

M^pro inhibitor

HCV

Preclinical

Suramin

M^pro inhibitor

Antiparasitic

Preclinical

Ebselen

M^pro inhibitor

HIV

Preclinical

GRL-0617

PL^pro inhibitor

SARS-CoV

Preclinical

Peking University team

Carmofur

M^pro inhibitor

Antineoplastic

Preclinical

Calpeptin

M^pro inhibitor

Calpain inhibitor

Preclinical

Pelitinib

M^pro inhibitor

Non-small-cell lung cancer

Preclinical

Wyeth

Darunavir

M^pro inhibitor

HIV

Preclinical

Tibotec

Sabizabulin

Prostatic cancer

Phase 3
NCT04842747

Veru

Proxalutamide

AR inhibitor

Prostatic cancer

Phase 3
NCT04728802
NCT04853134
NCT04870606 et al

Kintor

HC-1119

AR inhibitor

Prostatic cancer

Phase 3
NCT04986176

Hinova

Inhibitor	Reported mechanism of action	Testing model	Activity IC₅₀/EC₅₀/μmol·L^-1	Toxicity CC₅₀/μmol·L^-1	Clinical information	Ref.
11a (DC402234/FB2001)	M^pro	In vitro	0.053	> 100	Phase 1 NCT05197179 NCT04766931	[93]
11b	M^pro	In vitro	0.040	> 100	Preclinical	[93]
MI-09	M^pro	In vitro	0.86	> 500	Preclinical	[94]
MI-30	M^pro	In vitro	0.54	> 500	Preclinical	[94]
13b	M^pro	In vitro	0.67		Preclinical	[95]
N3	M^pro	In vitro	16.77		Preclinical	[81]
PF-07321332	M^pro	In vitro	0.21	> 50	Paxlovid obtain FDA EUA	[96]
S-217622	M^pro	In vitro	0.29		Phase 3 NCT05305547	[98]
PBI-0451	M^pro				Phase 1 NCT05011812
EDP-235	M^pro				Phase 1 NCT05246878
SIM0417 (SSD8432)	M^pro				Phase 1 NCT05339646
BE-33	E	In vitro	0.94	31.46	Preclinical	[97]
RAY003					Preclinical

Inhibitor

Reported mechanism of action

Testing model

Activity IC₅₀/EC₅₀/μmol·L^-1

Toxicity CC₅₀/μmol·L^-1

Clinical information

Ref.

11a (DC402234/FB2001)

M^pro

In vitro

0.053

> 100

Phase 1
NCT05197179
NCT04766931

[93]

11b

M^pro

In vitro

0.040

> 100

Preclinical

[93]

MI-09

M^pro

In vitro

0.86

> 500

Preclinical

[94]

MI-30

M^pro

In vitro

0.54

> 500

Preclinical

[94]

13b

M^pro

In vitro

0.67

Preclinical

[95]

M^pro

In vitro

16.77

Preclinical

[81]

PF-07321332

M^pro

In vitro

0.21

> 50

Paxlovid obtain FDA EUA

[96]

S-217622

M^pro

In vitro

0.29

Phase 3
NCT05305547

[98]

PBI-0451

M^pro

Phase 1
NCT05011812

EDP-235

M^pro

Phase 1
NCT05246878

SIM0417 (SSD8432)

M^pro

Phase 1
NCT05339646

BE-33

In vitro

0.94

31.46

Preclinical

[97]

RAY003

Preclinical

Peptide	Sequence	Tesing mode	IC₅₀/EC₅₀ /μmol·L^-1	CC₅₀ /μmol·L^-1	Ref.
EK1	SLDQINVTFLDLEYEMKKLEEAIKKLEESYIDLKEL	In vitro	2.468		[120]
EK1C4	EK1-GSGSG-PEG4-Chol	In vitro	0.036 5		[120]
EKL1C	NVTFLDLEYEMKKLEEAIKKLEESYIDLKELGTYEY-GSG-C(Chol)	In vitro	0.045	10	[121]
N-0385	Ms-Gln-Phe-Arg-kbt	In vitro	2.3	3 470	[123]
2019-nCoV-HR2P	DISGINASVVNIQKEIDRLNEVAKNLNESLIDLQEL	Pseudovirus	0.18		[118]
[SARS_HRC-PEG₄]₂-Chol	[DISGINASVVNIQKEIDRLNEVAKNLNESLIDLQEL-PEG₄]₂-Chol	In vitro	~0.3	> 100	[122]

Peptide

Sequence

Tesing mode

IC₅₀/EC₅₀ /μmol·L^-1

CC₅₀ /μmol·L^-1

Ref.

EK1

SLDQINVTFLDLEYEMKKLEEAIKKLEESYIDLKEL

In vitro

2.468

[120]

EK1C4