本文短链接：gettr.ink/eCsccZ

1.什么是青蒿素及其衍生物 Artemisinin and its derivatives

青蒿素是一种来源于植物黄花蒿的倍半萜类化合物，具有抗感染、免疫调节、抑制肿瘤细胞等多种生物活性。Artemisinin is a sesquiterpene compound derived from the plant Artemisia annua, which has various biological activities such as anti-infection, immune regulation, and tumor cell inhibition.

1.1 青蒿素中医药背景及历史沿革 Background of artemisinin in traditional Chinese medicine and its development

20世纪60年代，随着传统抗疟药物耐药性的出现，全球迫切需要新型抗疟药物。1971年下半年，中国中医研究院的屠呦呦领导的科研小组从中国传统医学典籍受到了启发，以乙醚提取其中的有效成分。1971年10月4日研究组取得青蒿中性提取物对鼠疟、猴疟100%疟原虫抑制率的突破。In the second half of 1971, the scientific research team led by Tu Youyou of the China Academy of Traditional Chinese Medicine was inspired by the classics of traditional Chinese medicine and extracted the active ingredients with ether. On October 4, 1971, the research team achieved a breakthrough in the 100% inhibition rate of malaria parasites by the neutral extract of Artemisia Annua on rat malaria and monkey malaria.

1977年《科学通报》第22卷第3期以“青蒿素结构研究协作组”的名义，首次发表了青蒿素化学结构及相对构型的论文，题目是《一种新型的倍半萜内酯——青蒿素》。青蒿素的结构完全公诸于世 [1]。The “Science Bulletin”, Volume 22, No. 3, of 1977 saw a publication with the authorship of “Artemisinin Structure Research Collaborative Group”. This publication reported the chemical structure and relative configuration of artemisinin for the first time, titled “A New Type of Sesquiterpene Lactone-artemisinin”. The structure of artemisinin is fully known to the world [1].

1.2 青蒿素及其衍生物代谢特性 Metabolic properties of artemisinin and its derivatives

青蒿素为脂溶性化合物，口服生物利用度较低。因此在其原有结构的基础上，研究人员开发了诸多结构优良的衍生物。其中有代表性的是蒿甲醚、青蒿琥酯。Artemisinin is a fat-soluble compound with low oral bioavailability. Based on its unique structure, researchers have developed many derivatives with excellent structures. Among them, artemether and artesunate are representative.

青蒿素和青蒿素衍生物有着不同的代谢途径。群体药动学研究显示，青蒿素具有肝药酶诱导效应，这显示在口服青蒿素后，自第二日起青蒿素在体内的药物暴露逐渐降低，这一过程往往在停药后两到三周内恢复正常[2]。药物相互作用研究显示，口服青蒿素会降低青蒿素衍生物在体内的药物暴露，但口服青蒿琥酯后并不会降低青蒿素在体内的药物暴露[3]。Artemisinin and artemisinin derivatives have different metabolic pathways. Population pharmacokinetic studies have shown that artemisinin has a Cytochrome-inducing effect, which results in a low artemisinin exposure one day after oral dose of artemisinin. The drug exposure gradually decreases from the second day onwards. This process tends to resume within two to three weeks [2]. Drug interaction studies have shown that oral administration of artemisinin can reduce the drug exposure of artemisinin derivatives, but oral administration of artesunate does not reduce the drug exposure of artemisinin [3].

青蒿琥酯口服后，部分在肠道依赖酸的化学水解作用形成双氢青蒿素后再吸收入血液中；未转化的部分则直接通过门静脉进入肝脏，此部分有些再通过肝脏代谢青蒿素的过程被转化为双氢青蒿素。青蒿琥酯具有水溶性，有利于吸收，具有其他青蒿素衍生物没有的药物动力学优势 。鉴于其优秀的理化性质，青蒿琥酯可以制成各类制剂，如注射液、片剂、栓剂、脂质体微囊等，用于注射、口服或直肠给药，甚至可以经静脉滴注进行全身给药。青蒿琥酯是一种速效、低毒的抗疟药物，用于成人、儿童以及孕妇的疟原虫感染治疗，已挽救了数百万人的生活 [4]。After oral administration of artesunate, part of it will be absorbed into the blood after being formed into dihydroartemisinin by the chemical hydrolysis of acid in the intestinal tract, and the untransformed part will directly enter the liver through the portal vein, and part of it will be converted into dihydroartemisinin through liver metabolism Artemisinin. Artesunate is water-soluble, which is beneficial to absorption, and has pharmacokinetic advantages that other artemisinin derivatives do not have. In view of its excellent physical and chemical properties, artesunate can be made into various preparations, such as injections, tablets, suppositories, liposome microcapsules, etc., for injection, oral or rectal administration, and even intravenous infusion For systemic administration. Artesunate is a fast-acting, low-toxicity antimalarial drug used in the treatment of Plasmodium infection in adults, children and pregnant women, and has saved millions of lives [4].

2. 青蒿素及其衍生物的药理机制 Pharmacological mechanism of artemisinin and its derivatives

2.1 青蒿素及其衍生物的抗疟机理 Antimalaria activity of Artemisinins

作为一线抗疟药，青蒿素安全、低毒、耐受性好。 最常见的青蒿素衍生物包括蒿甲醚、蒿乙醚、双氢青蒿素、及青蒿琥酯。 它们被作为疟疾联合疗法的一部分在全世界销售。其相关药理机制在1972 年由中国科学家屠呦呦领衔的科研团队发现，并以此获得 2015 年诺贝尔生理医学奖 [5]。As first-line antimalarial medicines, Artemisinins are safe, low-toxic, and tolerable. The most common Artemisinin derivatives include artemether, arteether, dihydroartemisinin, and artesunate. They are marketed as part of combination therapy throughout the world. Its pharmacological mechanism was discovered in 1972 by a research team led by Chinese scientist Tu Youyou and thus shared the 2015 Nobel Prize in Physiology or Medicine [5].

青蒿素及其衍生物都是含有特殊的过氧化物桥的倍半萜内酯。这种内过氧化物环是其抗疟疾特性的关键。青蒿素及其衍生物已用于治疗疟疾和寄生虫（蠕虫）感染。其机理是青蒿素及其衍生物结合寄生虫细胞内的铁，催化过氧化物桥的崩解，然后产生大量自由基，最后导致寄生虫蛋白质破坏而起作用 [6]。青蒿素及其衍生物药效快，可杀死所有疟原虫物种的血液阶段并减少寄生虫生物量 [7,8]。Artemisinins appear to act by binding iron, breaking down peroxide bridges and generating free radicals that damage parasite proteins. They work rapidly, killing the blood stages of all Plasmodium species and reducing the parasite biomass [6]. Artemisinins have the fastest parasite clearance times of any antimalarial [7,8].

虽然口服蒿甲醚和双氢青蒿素（DHA）比青蒿琥酯更常被使用在固定剂量的处方中[9]。 但是在药物稳地性以及易于联合用药的表现上，青蒿琥酯优于双氢青蒿素（DHA）；且在动物实验的不良反应结果上，青蒿琥酯优于蒿甲醚。因此，静脉注射青蒿琥酯是治疗重症疟疾的一线疗法 [10]。 青蒿琥酯在治疗严重疟疾方面也优于奎宁，其清除寄生虫血症和降低儿童和成人死亡率的效果更优 [11]。 青蒿琥酯直肠给药也广泛用于疟疾流行的偏远地区，可以有效稳定重症患者病情，直到将患者转运到专业医疗机构进行治疗 [12]。Oral artemether and dihydroartemisinin (DHA) are more commonly used in fixed-dose formulations than artesunate [9]. Artesunate might have more favorable properties, both in terms of stability and ease of co-formulation, when compared with DHA, and adverse effects in animal models, when compared with artemether. Intravenous artesunate is the first-line therapy for the treatment of severe malaria [10]. It is superior to quinine for treating severe malaria-clearing parasitemia and reducing mortality in children and adults [11].  Rectal artesunate is used in remote areas of malaria-endemic countries for stabilizing severely ill patients before health facility transport for further management [12].

2.2 青蒿素及其衍生物的抗病毒机理 Antiviral Mechanism of Artemisinin and Its Derivatives

青蒿素及其衍生物（ARTs）是目前最瞩目的抗病毒候选药物，其在低微摩尔范围内就具有抗乙型和丙型肝炎病毒、人类疱疹病毒一型和二型、人免疫缺陷病毒、EB病毒、以及甲型流感病毒的活性,并在联合使用时与其他抗病毒药物具有协同作用 [13-20]。通常，ARTs 会抑制病毒感染细胞的关键代谢调节通路（NF-κB 或 Sp1 依赖性通路），从而阻断病毒感染特异性宿主细胞以及在细胞内复制扩增 [21]。ARTs have turned out to be the most promising antiviral drug candidates with activities against hepatitis B and C viruses, human herpes viruses HSV-1 and HSV-2, HIV-1, Epstein-Barr, and influenza virus A in the low micromolar range and is synergistic with other antiviral drugs when used in combination \[13-20\]. In most cases, ARTs inhibited the central regulatory processes of viral-infected cells (NF-κB or Sp1-dependent pathways), thus blocking the host-cell–type and metabolic requirements for viral replication [21].

来自不同种类的蒿属植物的提取物对 SARS-CoV-2 都具有活性。体外试验证明青蒿素及其衍生物（ARTs）可有效抑制 SARS-CoV-2 在细胞内扩增 [22]；青蒿琥酯可有效结合 SARS-CoV-2 的刺突蛋白的 Lys353 和 Lys31 位点，其效果优于羟氯喹[23]。计算机模拟和蛋白分子实验研究也显示，与羟氯喹相比，ARTs可以更有效地结合多个COVID-19 靶蛋白，包括刺突糖蛋白、刺突胞外域结构蛋白、主要蛋白酶 (MPro)，以及刺突蛋白受体结合域，从而阻止 SARS-CoV-2 与宿主受体 ACE2 结合 [24-31]。 因此提示，ARTs 可以作为防治 SARS-CoV-2 感染优先选择药物 [32,33]。Recently, several investigators have now shown that extracts from different species of Artemisia are active against SARS-CoV-2. In vitro experiments have shown that artemisinin and its derivatives can effectively inhibit the intracellular amplification of SARS-CoV-2 [22]; artesunate can effectively bind to Lys353 and Lys31 sites of the Spike protein of SARS-CoV-2, and its effect is stronger than that of hydroxy-chloroquine [23]. Researchers used in silico approaches to investigate if artemisinin or its derivatives could physically bind any of the COVID-19 target proteins including SARS-CoV-2 spike glycoprotein, spike ectodomain structural protein, the main protease of the virus (MPro) or spike receptor-binding domain, thereby preventing SARS-CoV-2 from binding to the host receptor ACE2. Furthermore, molecular docking studies revealed that artemisinin bound to all four proteins and in some cases displayed better binding modes than hydroxychloroquine [24-31]. Thus, ARTs could serve as best leads for further drug development process for SARS-CoV-2 infection [32，33].

青蒿素及其衍生物（ARTs）也可通过调节宿主细胞TGF-β代谢途径，进而降低 SARS-CoV-2 病毒在细胞内的扩增。其抗病毒活性的机制可能是通过诱导细胞 ROS、钝化 PI3K/Akt/p70S6K 信号通路、结合 NF-κB/Sp1 或诱导内吞抑制机制，从而抑制病毒的复制和生长 [34]。Results from recent studies indicate that ARTs impair SARS-CoV-2 viral infection by modulating several host cell TGF-β metabolic pathways, thus making them attractive candidates for COVID-19. The mechanism of antiviral activity may be through the induction of cellular ROS, blunting the PI3K/Akt/p70S6K signaling pathway, binding to NF-κB/Sp1 or inducing an endocytosis inhibition mechanism, all of which lead to inhibition of viral replication and growth [34].

2.3 青蒿素及其衍生物的免疫调节效应 Immunomodulatory effects of ARTs

青蒿素及其衍生物（ARTs）具有明确的抗炎和免疫调节作用，能降低多种炎症因子的水平，抑制自身免疫性炎症，细菌感染性炎症，以及COVID-19引发的炎症和细胞因子风暴的发生发展 [35]。ARTs were proven for their potent anti-inflammatory and immunomodulatory effects, which can reduce various inflammatory factors levels, and inhibit autoimmune inflammation, bacterial infectious inflammation, and the occurrence of inflammation and cytokine storm caused by COVID-19 development [35].

动物研究发现可有效治疗多种自身免疫性炎症，包括类风湿性关节炎、系统性红斑狼疮、多发性硬化症、炎性肠病、以及过敏性疾病 [36]。 其抗炎机制包括：

(1）抑制 iNOS 和 COX-2 通路；

(2) 抑制 ERK 和 NF-κB 信号；

(3)抑制病原性T细胞活化；

(4)抑制B细胞活化和抗体产生；

(5) 通过 TNF-α 下游的 PI3K/Akt 信号通路抑制 Akt 磷酸化和 IκB 降解。

因此，青蒿素及其衍生物（ARTs）可作为炎症性疾病和自身免疫性疾病的候选治疗方案 [37]。

ARTs exhibit potent anti-inflammatory effects. Using animal models, Artemisinins effectively treated autoinflammatory conditions, including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and allergic disorders [36]. Some of the anti-inflammatory mechanisms include

(1) inhibition of the iNOS and COX-2 pathways;

(2) suppression of ERK and NF-κB signaling;

(3) inhibition of pathogenic T cell activation;

(4) suppressing B cells activation and antibody production; and

(5) inhibition of Akt phosphorylation and IκB degradation through the PI3K/Akt signaling pathway downstream of TNF-α.

Thus, the varied mechanisms of ARTs exhibit their anti-inflammatory effects warrant investigation into their role as therapeutic candidates for inflammatory conditions and autoimmune disorders [37].

SARS-CoV-2 感染伴随着细胞因子风暴以及感染末期的水肿和肺纤维化。 SARS-CoV-2 诱导 TGF-β 的表达上调，可能是肺纤维化的诱因 [38]。 人们急切希望找到即可有效阻断 TGF-β 又低毒性的小分子。 令人鼓舞的是，在几种炎症性疾病模型中，青蒿素及其衍生物（ARTs）都被证明可以有效抑制 TGF-β [34]。Transforming Growth Factor-beta (TGF-β) plays an important role in modulating the immune system and displays different activities on different types of immune cells. SARS-CoV-2 infection is accompanied by a cytokine storm together with edema and pulmonary fibrosis at the end stage of the infection. SARS-CoV-2 also up-regulates TGF-β expression which may partly explain the cytokine storm and fibrosis in the lung [38]. Efforts are underway to discover novel and specific small molecules that can potently block TGF-β expression with negligible side-effects. Artemisinin and its derivatives have been shown to be suppressors of TGF-β in several models of inflammatory diseases [34].

2.4 青蒿素衍生物抗癌前景 Anti-tumor activity of Artemisinins

青蒿素及其衍生物（ARTs）的抗肿瘤作用机制主要涉及诱导细胞凋亡。ARTs 的过氧化物桥药效团可被血红素或游离亚铁还原，从而产生碳自由基和活性氧 (ROS)。过量的 ROS 会导致细胞凋亡[39,40]。除此以外，ARTs 也可以通过诱导非凋亡途径，导致细胞死亡（包括自噬和铁死亡），进而发挥抗肿瘤活性 [41-43]。此外，ARTs 也可阻滞癌症发生发展的多个关键进程，包括抑制癌细胞增殖、抗血管生成、抗癌转移和侵袭、诱导细胞周期停滞、破坏癌症信号通路和打乱肿瘤微环境 [44,45]。The mechanism of anti-tumor action of Artemisinins is mainly involved in apoptotic cell death which has been confirmed by most literature. Recognized endoperoxide bridge pharmacophores could be reduced by heme or free ferrous iron to generate carbon-free radicals and reactive oxygen species (ROS). Excess production of ROS is known to cause apoptotic cell death [39,40]. However, new mechanisms of action in the anti-tumor activity of ARTs by affecting non-apoptotic cell death, including autophagy, and ferroptosis, were also found [41-43]. ARTs, including the suppression of cancer cell proliferation, anti-angiogenesis, anti-cancer metastasis and invasion, induction of cell cycle arrest, disruption of the cancer signaling pathway, and regulation of tumor microenvironment, also influenced other hallmark events of cancer development and progression [44,45].

迄今为止，已有大量体外和体内研究描述了 ARTs 的抗癌作用，并取得了令人鼓舞的结果 [46]。 研究人员通过开发新型青蒿素衍生物、包装青蒿素纳米制剂、以及联合疗法等手段推进青蒿素的癌症治疗 [47]。已有多份病例报道，描述 ARTs 抑制肿瘤生长的效益。相关研究主要为实体肿瘤，包括结直肠癌、乳腺癌、肝细胞癌、前列腺癌和肺癌 [48-52]。 多项针对不同肿瘤的 1期（安全性）和 2期（小样本有效性）临床试验正在多家临床机构中开展。Recent ARTs anticancer therapies include developing novel ARTs derivatives, novel nano-formulations, and combination therapy [46]. There are many encouraging in vitro and in vivo studies describing the ARTs anticancer effects [47]. Many case reports documented ARTs on reducing tumor size and retarding growth. The most well-studied are solid tumors: colorectal carcinoma, breast cancer, hepatocellular carcinoma, and lung cancer [48-52]. Several phase 1 (safety) and phase 2 (small sample efficacy) clinical trials targeting different tumors are being conducted in multiple clinical institutions.

3. 青蒿素衍生物对Covid-19的防治建议 Suggestions on the Prevention and Treatment of Artemisinin Derivatives against Covid-19

3.1 已有临床研究结果 Documented clinical research results

2020年，一项收治43例新冠肺炎确诊患者，18例纳入青蒿琥酯联合治疗组，25例为常规治疗组。结果显示, 青蒿琥酯联合治疗组的病灶吸收时间增快（青蒿琥酯14.11±4.16天，对照17.04±4.42天）住院时间缩短（青蒿琥酯16.56±3.71天，对照18.04±3.97天）。该结果表明青蒿琥酯能缩短新冠肺炎患者的治疗时间，改善预后和清除病原体，不良反应少，有很好的应用前景 [52]。由于青蒿琥酯具有双向免疫调节作用，因此有利于减轻SARS-CoV-2引发的脓毒症,从而降低 Covid-19 重症、危重症患者的病死率 [54]。In 2020, a chinese clinic trial recruded 43 Covid-19 patients,of which 18 were treated with artesunate combination treatment and 25 with conventional. According to the results, the artesunate combination treatment group showed faster lesion absorption (day: 14.11±4.16 vs 17.04±4.42) and shorter hospital stay (day: 16.56±3.71 vs 18.04±3.97). It indicated that artesunate can shorten the Covid-19 treatment time, clear pathogens, and improve prognosis with minimized adverse effects [52]. Artesunate is beneficial to reduce the sepsis caused by SARS-CoV-2,by its duo-immunomodulatory effects, thereby, reduce the mortality rate of severe and critically ill patients with Covid-19 [54].

另一项2020年，收治41例Covid-19确诊病例的临床对照试验中，23名受试者接受青蒿素\-哌喹的治疗组合，另18名受试者为对照组。青蒿素\-哌喹组的第一天口服负荷剂量为两片（青蒿素 125 毫克和哌喹 750 毫克），然后每天服用一片低剂量（青蒿素 62.5 毫克和哌喹 375 毫克），持续六天。结果表明：青蒿素\-哌喹组的SARS-CoV-2病毒检测、清除速率明显快于对照组，且住院时间明显缩短。该研究证明青蒿素\-哌喹的低毒性和免疫调节性可使其治疗Covid-19的优选药物 [55]。In 2020，another controlled clinical trial published its results. It included 41 confirmed Covid-19 patients. While 18 subjects served as the control group, the experimental group (n = 23) received a combination of artemisinin-piperaquine (AP). AP was orally administrated with a loading dose of two tablets (artemisinin 125 mg and piperaquine 750 mg) on the first day, followed by a low dose of one tablet/day (artemisinin 62.5 mg and piperaquine 375 mg) for six days. The results indicated the AP group’s significantly faster SARS-CoV-2 RNA undetectable time and higher elimination rate, as well as, much shorter length of hospital stay. The safe toxicity profile and immunoregulatory activities makes AP an excellent drug candidate against SARS-CoV-2 infection [55].

3.2 进展中的临床试验 Clinical Trials in Progress

美国临床试验网站上注册编号为 NCT04387240 的一项临床试验项目“评估青蒿琥酯对 轻度COVID-19 成人的疗效”[56] 。在此临床试验中，COVID-19 检测阳性的患者或将接受100毫克/日计量的青蒿琥酯，研究人员将采用随机双盲的方法评估青蒿琥酯改善 COVID-19 症状以及清除病毒载量的效力。In an ongoing clinical trial entitled: Evaluating the Efficacy of Artesunate in Adults with Mild Symptoms of COVID-19 (#NCT04387240), patients with mild Covid-19 symptoms will randomly receive 100 mg/day of artesunate or placebo.Investigators will evaluate artesunate efficiency by measuring the improvement of Covid-19 condition and clearing the virus load in a randomized double-blind method [56].

参考文献 References

[1]  Coordinating Research Group for the structure of artemisinin (1977) A new type of sesquiterpene lactone-artemisinin. Chin Sci Bull 22:142 (in Chinese).

[2]  Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Mol Pharmacol. 2005 Jun;67(6):1954-65. doi: 10.1124/mol.104.009019. Epub 2005 Mar 10. PMID: 15761118.

[3]  Artemisinin derivatives,J.K. Aronson, Meyler's Side Effects of Drugs (Sixteenth Edition), 2016,Pages 701-710, ISBN 9780444537164.

[4]  岑彦艳,赵祎博,李攀,等. 青蒿琥酯的药代动力学以及相关药理作用研究进展\[J\]. 中国中药杂志, 2018, 43(19): 3970-3978.

[5]  https://www.nobelprize.org/prizes/medicine/2015/tu/facts/

[6]  Artemisinins target the SERCA of Plasmodium falciparum. Nature. 2003;424(6951):957.

[7]  Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrob Agents Chemother. 1997;41(7):1413.

[8]  Clinical pharmacokinetics and pharmacodynamics of artemisinin and derivatives. Trans R Soc Trop Med Hyg. 1994;88 Suppl 1:S41.

[9]  Anti-inflammatory and immunoregulatory functions of artemisinin and its derivatives. Mediators Inflamm. 2015;2015 Structurally diverse sesquiterpenoids from the aerial parts of Artemisia annua (Qinghao) and their striking systemically anti-inflammatory activities. Bioorg. Chem. 2020;103:104221.

[10]Mechanisms of Artemisia scoparia’s anti-inflammatory activity in cultured adipocytes, macrophages, and pancreatic β-cells. Obesity. 2020;28:1726–1735

[11]Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010;376(9753):1647. Epub 2010 Nov 7.

[12]Rectal artemisinins for malaria: a review of efficacy and safety from individual patient data in clinical studies. BMC Infect Dis. 2008;8:39. Epub 2008 Mar 28.

[13]Artemisinin analogues as potent inhibitors of in vitro hepatitis C virus replication. PLoS ONE. 2013;8:e81783

[14]Effect of artemisinin/artesunate as inhibitors of hepatitis B virus production in an ”in vitro” replicative system. Antiviral Res. 2005;68:75–83.

[15]Could be an alternative drug to chloroquine in COVID-19 treatment? Chin. Med. 2020;15:54.

[16]The antiviral activities of artemisinin and artesunate. Clin. Infect. Dis. 2008;47:804–811.\]

[17]The use of antimalarial drugs against viral infection. Microorganisms. 2020;8:85.

[18]A survey of therapeutic effects of Artemisia capillaris in liver diseases. Evid. Based Complement. Alternat. Med. 2015;2015

[19]Marschall M. The antiviral activities of artemisinin and artesunate. Clin. Infect. Dis. 2008;47:804–811.

[20]Auerochs S, Korn K, Marschall M. A reporter system for Epstein-Barr virus (EBV) lytic replication: anti-EBV activity of the broad anti-herpesviral drug artesunate. J Virol Methods. 2011 May;173(2):334-9.

[21]Phytocompounds of Rheum emodi, Thymus serpyllum and Artemisia annua inhibit COVID-19 binding to ACE2 receptor: In silico approach. Res. Square. 2020

[22]Hu Yunjia,Liu Meiqin,Qin Hongbo,Lin Haofeng,An Xiaoping,Shi Zhengli,Song Lihua,Yang Xinglou,Fan Huahao,Tong Yigang. Artemether, Artesunate, Arteannuin B, Echinatin, Licochalcone B and Andrographolide Effectively Inhibit SARS-CoV-2 and Related Viruses In Vitro\[J\]. Frontiers in Cellular and Infection Microbiology,2021,11.

[23]Sehailia Moussa,Chemat Smain. Antimalarial-agent artemisinin and derivatives portray more potent binding to Lys353 and Lys31-binding hotspots of SARS-CoV-2 spike protein than hydroxychloroquine: potential repurposing of artenimol for COVID-19.\[J\]. Journal of biomolecular structure & dynamics, 2020, (16): 6184-6194.

[24]In-silico drug repurposing for targeting SARS-CoV-2 Mpro. J. Biomol. Struct. Dyn. 2020

[25]Anti-SARS-CoV-2 potential of artemisinins in vitro. ACS Infect. Dis. 2020;6:2524–2531.

[26]Repurposing Artemisia annua L. flavonoids, artemisinin and its derivatives as potential drugs against novel coronavirus (SARS-nCoV) as revealed by in-silico studies. Int. J. Appl. Sci. Biotechnol. 2020;84:374–393.

[27]Screening of preferential binding affinity of selected natural compounds to SARS-CoV-2 proteins using in silico methods. EJMO. 2020;4:319–323.

[28]Molecular basis for drug repurposing to study the interface of the S protein in SARS-CoV-2 and human ACE2 through docking, characterization, and molecular dynamics for natural drug candidates. J. Mol. Model. 2020;26:338.

[29]Repurposing Artemisia annua L. flavonoids, artemisinin and its derivatives as potential drugs against novel coronavirus (SARS-nCoV) as revealed by in-silico studies. Int. J. Appl. Sci. Biotechnol. 2020;84:374–393.

[30]Screening of preferential binding affinity of selected natural compounds to SARS-CoV-2 proteins using in silico methods. EJMO. 2020;4:319–323.

[31]Molecular basis for drug repurposing to study the interface of the S protein in SARS-CoV-2 and human ACE2 through docking, characterization, and molecular dynamics for natural drug candidates. J. Mol. Model. 2020;26:338.

[32]Artemisia annua L. extracts prevent in vitro replication of SARS-CoV-2. BioRxiV. 2020。

[33]Anti-SARS-CoV-2 potential of artemisinins in vitro. ACS Infect. Dis. 2020;6:2524–2531.

[34]A potential treatment of COVID-19 with TGF-beta blockade. Int J. Biol. Sci. 2020;16:1954–1955.

[35]刘桂梅,蔡楠,谢静,等. 青蒿素及其衍生物用于治疗新型冠状病毒肺炎的探讨\[J\]. 药物评价研究, 2020, 43(4): 606-612.

[36]Anti-inflammatory and immunoregulatory functions of artemisinin and its derivatives. Mediators Inflamm. 2015;2015 Structurally diverse sesquiterpenoids from the aerial parts of Artemisia annua (Qinghao) and their striking systemically anti-inflammatory activities. Bioorg. Chem. 2020;103:104221.

[37]Mechanisms of Artemisia scoparia’s anti-inflammatory activity in cultured adipocytes, macrophages, and pancreatic β-cells. Obesity. 2020;28:1726–1735

[38]Selectively targeting TGF-β with trabedersen/OT-101 in treatment of evolving and mild ARDS in COVID-19. Clin. Investig. 2020;10:167–176.

[39]Artemisinin enhances the anti-tumor immune response in 4T1 breast cancer cells in vitro and in vivo. Int. Immunopharmacol. 2019;70:110–116.

[40]The anti-malarial drug artesunate causes cell cycle arrest and apoptosis of triple-negative MDA-MB-468 and HER2-enriched SK-BR-3 breast cancer cells. Exp. Mol. Pathol. 107, 10–22.

[41]Artesunate induces oncosis-like cell death in vitro and has antitumor activity against pancreatic cancer xenografts in vivo. Cancer Chemother. Pharmacol. 65, 895–902.[42]Artesunate inhibits the growth of gastric cancer cells through the mechanism of promoting oncosis both in vitro and in vivo. Anti-cancer Drugs 24, 920–927.

[43]Artemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cells. Phytomedicine 22, 1045–1054.

[44]Dihydroartemisinin induces autophagy-dependent death in human tongue squamous cell carcinoma cells through DNA double-strand break-mediated oxidative stress. Oncotarget 8, 45981–45993.

[45]Artesunate induces apoptosis and autophagy in HCT116 colon cancer cells, and autophagy inhibition enhances the artesunateinduced apoptosis. Int. J. Mol. Med. 42, 1295–1304.[46]From ancient herb to modern drug: Artemisia annua and artemisinin for cancer therapy. Semin. Cancer Biol. 46, 65–83.

[47]Antitumor Research on Artemisinin and Its Bioactive Derivatives. Nat. Prod. Bioprospect. 8, 303–319.

[48]Case report of a laryngeal squamous cell carcinoma treated with artesunate. Arch Oncol 10(4): 279-280, 2002

[49]Effects of dihydroartemisinin, a metabolite of artemisinin, on colon cancer chemoprevention and adaptive immune regulation. Molecular Biology Reports volume 49, pages2695–2709

[50]Antiproliferative effects of artemisinin on human breast cancer cells requires the downregulated expression of the E2F1 transcription factor and loss of E2F1-target cell cycle genes. Anticancer Drugs. 2012 Apr;23(4):370-9.

[51]Artemisinin suppresses hepatocellular carcinoma cell growth, migration and invasion by targeting cellular bioenergetics and Hippo-YAP signaling. Arch Toxicol, 2019 Nov;93(11):3367-3383.

[52]Artemisinin and its derivatives can significantly inhibit lung tumorigenesis and tumor metastasis through Wnt/β-catenin signaling. Oncotarget. 2016 May 24; 7(21): 31413–31428.

[53]林艳荣,吴锋耀,谢周华,等. 青蒿琥酯治疗新型冠状病毒肺炎的临床研究[J]. 中华危重病急救医学, 2020, 32(4): 417-420.

[54]周红,李小丽,李斌. 重视2019冠状病毒病(COVID-19)诱导的脓毒症免疫抑制[J]. 第三军医大学学报, 2020, 42(6): 539-544.

[55]Safety and efficacy of artemisinin-piperaquine for treatment of COVID-19: An open-label, non-randomized, and controlled trial. Int J. Antimicrob. Agents. 2020;18:106216.

[56]https://clinicaltrials.gov/ct2/show/NCT04387240

青蒿素及其衍生物的药理机理以及临床用药.pdf