WO2021203706A1 - 膦甲酸钠在制备预防和治疗冠状病毒的药物中的应用 - Google Patents
膦甲酸钠在制备预防和治疗冠状病毒的药物中的应用 Download PDFInfo
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- WO2021203706A1 WO2021203706A1 PCT/CN2020/129212 CN2020129212W WO2021203706A1 WO 2021203706 A1 WO2021203706 A1 WO 2021203706A1 CN 2020129212 W CN2020129212 W CN 2020129212W WO 2021203706 A1 WO2021203706 A1 WO 2021203706A1
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- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Definitions
- the invention belongs to the field of antiviral drugs, and specifically relates to the application of foscarnet sodium in the preparation of drugs for the prevention and treatment of anti-coronavirus.
- New coronary pneumonia (COVID-19) is an infectious disease caused by a new type of coronavirus (SARS-Cov-2) infecting the human body. Its symptoms mainly include fever, fatigue, dry cough, dyspnea, and kidney failure. [The Lancet, 2020, 395(10223):507-513; The Lancet, 2020,395(10223):497-506]. New crown pneumonia began to report cases in December 2019, and then many countries, including South Korea, Japan, Thailand, Iran, Singapore, Germany, France, and the United States, have successively seen cases.
- SARS-Cov-2 coronavirus
- Coronaviruses belong to the genus Coronavirus in the family Coronaviridae (Coronaviridae).
- the virus of the genus Coronavirus is a positive-stranded single-stranded RNA virus with an envelope, with a diameter of about 80-120nm. Its genetic material is the largest among all RNA viruses, and generally only infects humans, mice, pigs, cats, and dogs. , Poultry vertebrates.
- the coronavirus was first isolated from chickens in 1937. Coronavirus particles are irregular in shape, about 60-220nm in diameter.
- SARS-Cov-2 virus particles The diameter of SARS-Cov-2 virus particles is between 60nm and 140nm, and there are 9-12nm spikes outside the envelope, resembling a corolla. Genome sequencing showed that SARS-Cov-2 is a single-stranded RNA coronavirus. By comparison with the gene sequences of other virus samples, it is found that SARS-Cov-2 is similar to SARS-CoV (79.5%) [Nature,2020] and bat coronavirus (96%) [bioRxiv,2020,2020.01.22.914952], and speculates The virus may originate from bats [bioRxiv, 2020, 2020.01.24.915157; Nature, 2020].
- the new type of coronavirus pneumonia is caused by a new type of coronavirus. It is the same type of coronavirus as SARS-CoV, which is known to cause atypical pneumonia, but is of a different type. Although its fatality rate is lower than SARS-CoV, it is far more infectious. In SARS-CoV. The global spread shows that the new coronavirus pneumonia epidemic still has the possibility of spreading. But so far, there is still no specific medicine that can cure the new type of coronavirus pneumonia. The development of effective antiviral drugs and vaccines has become the most urgent task at the moment. At present, the treatment of COVID-19 mainly relies on symptomatic adjuvant treatment, and there is still a lack of effective specific drugs and vaccines.
- Foscarnet sodium inhibits viral RNA polymerase, reverse transcriptase, and DNA polymerase by non-competitively inhibiting dNTPs, thereby inhibiting viral replication.
- Foscarnet sodium can effectively treat viral infections, such as skin infections, herpetic keratitis, genital infections, or infections throughout the body and brain.
- the present invention has carried out applied research on the antiviral efficacy of foscarnet sodium in coronavirus.
- the present invention provides foscarnet sodium or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs in the preparation of prevention and/or treatment of coronavirus. Application in disease-causing drugs.
- the coronaviruses are the new coronaviruses SARS-Cov-2, SARS-CoV, HCoV 229E, NL63, OC43, HKU1 and MERS-CoV.
- foscarnet sodium or its pharmaceutically acceptable salts, isotopes, stereoisomers, mixtures of stereoisomers, tautomers, esters, amides or prodrugs, and other antiviral drugs Application of the prepared composition as an active ingredient in preparing a medicine for preventing and/or treating diseases caused by coronavirus.
- Another aspect of the present invention provides a pharmaceutical composition for the treatment or prevention of diseases caused by coronaviruses, the pharmaceutical composition comprising foscarnet sodium or its pharmaceutically acceptable salts, isotopes, stereoisomers, and stereoisomers Mixtures of conformers, tautomers, esters, amides or prodrugs.
- the oral preparation is selected from granules, powders, pills, tablets, capsules or oral liquids.
- Another aspect of the present invention provides the use of foscarnet sodium as a disinfectant against coronaviruses of the coronavirus family.
- a disinfectant for eliminating coronavirus contamination of the coronavirus family includes foscarnet sodium.
- Another aspect of the present invention provides a method for treating diseases caused by viruses of the coronavirus family, comprising adding a therapeutically effective amount of foscarnet sodium or a pharmaceutically acceptable salt, isotope, stereoisomer, or stereoisomer A mixture of isomers, tautomers, esters, amides, or prodrugs are administered to the subject.
- Another aspect of the present invention provides a method for preventing a subject from being infected with coronaviruses of the coronavirus family, which comprises adding a therapeutically effective amount of foscarnet sodium or a pharmaceutically acceptable salt, isotope, stereoisomer, or stereoisomer.
- Administration of a mixture of conformers, tautomers, esters or prodrugs is administered to the subject prior to infection.
- the drug or pharmaceutical composition does not contain glucocorticoid or mineralocorticoid.
- the present invention finds for the first time that foscarnet sodium has an antiviral effect on the novel coronavirus, can block the novel coronavirus from infecting host cells, and can be used as a disease treatment for the treatment of anti-coronavirus infection.
- Foscarnet sodium anti-new coronary pneumonia new coronavirus drug efficacy evaluation The pharmacological effect of foscarnet sodium is evaluated by the CCK8 method, and the half effective concentration (EC 50 ) of the new coronary pneumonia new coronavirus (SARS-Cov-2) is 0.89 ⁇ M, which has low toxicity , Has a good treatment window.
- the African green monkey kidney cells (VeroE6) were inoculated into 96-well plates at 3 ⁇ 10 5 cells/well, and placed in the minimum Eagle's medium (MEM; GibcoInvitrogen) containing 10% fetal bovine serum (FBS; GibcoInvitrogen). Incubate at 37°C with 5% CO 2 until the monolayer grows up. A 100-fold dilution of the novel coronavirus clinical isolates of the novel coronavirus pneumonia was inoculated into a 96-well plate full of monolayer cells, and cultured at 37°C and 5% CO 2 for two days (including the normal control group).
- MEM minimum Eagle's medium
- FBS fetal bovine serum
- the degree of disease was as high as 75%, placed in a -80°C ultra-low temperature refrigerator, repeated freezing and thawing once, collecting the amplified virus solution, centrifuged at 3000r/min for 30 minutes, removing the sediment, and placing the small tubes in the -80°C ultra-low temperature refrigerator Long-term preservation.
- the foscarnet powder is dissolved in DMSO, it is added to the culture solution and diluted to 20mg/mL.
- the final concentration of DMSO is 1%. It is filtered through a 0.22 ⁇ m membrane and stored at 4°C; after filtration, it is stored at 4°C. Inoculate about 2.5 ⁇ 10 4 cells per well into a 96-well plate. After 24 to 48 hours, when the cells grow into a monolayer, discard the culture medium, add 100 ⁇ L/well of drugs of different dilutions, and 100 ⁇ L/well for normal cell control wells.
- VeroE6 cells were cultured overnight in a 48-well cell culture dish with a density of 5 ⁇ 10 4 cells/well.
- Virus MOI of 0.05
- Virus MOI of 0.05
- each concentration is set with 4 replicate wells, with 200 ⁇ M as the initial concentration of the drug, incubate for 2 days in a 34°C, 5% CO 2 incubator.
- CPE Cytopathogenic Effect
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
膦甲酸钠在制备预防和治疗冠状病毒的药物中的应用，具体公开了膦甲酸钠或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药在制备预防和/或治疗冠状病毒所致疾病的药物中的应用。所述的冠状病毒为新型冠状病毒SARS-Cov-2、SARS-CoV、HCoV 229E、NL63、OC43、HKU1和MERS-CoV。膦甲酸钠对新冠肺炎新型冠状病毒的半数有效浓度为0.89μM，治疗指数为449.43，表明具有一个良好的治疗窗口。
Description
本发明属于抗病毒药物领域，具体涉及膦甲酸钠在制备预防和治疗抗冠状病毒的药物中的应用。
新冠肺炎(COVID-19)是由新型冠状病毒(SARS-Cov-2)感染人体而引起的传染性疾病，其症状主要包括发热、乏力、干咳、呼吸困难和肾衰竭等[The Lancet,2020,395(10223):507-513；The Lancet,2020,395(10223):497-506]。新冠肺炎于2019年12月开始有报道病例，随后多个国家，包括韩国、日本、泰国、伊朗、新加坡、德国、法国和美国等也陆续出现病例。
冠状病毒在系统分类上属冠状病毒科(Coronaviridae)冠状病毒属(Corona virus)。冠状病毒属的病毒是具外套膜(envelope)的正链单股RNA病毒，直径约80～120nm，其遗传物质是所有RNA病毒中最大的，一般只会感染人、鼠、猪、猫、犬、禽类脊椎动物。冠状病毒于1937年被首次从鸡身上分离出来。冠状病毒粒子形状并不规则，直径约60～220nm。病毒具有包膜结构，上面有三种蛋白：刺突糖蛋白(S，Spike Protein)、小包膜糖蛋白(E，Envelope Protein)和膜糖蛋白(M，Membrane Protein)，少数种类还有血凝素糖蛋白(HE蛋白，Haemaglutinin－esterase)[NederlandsTijdschriftVoorGeneeskunde,2014,158(158):A8119-A8119]。
SARS-Cov-2病毒颗粒直径在60～140nm之间，包膜外有9～12nm的尖刺，形似花冠。基因组测序表明，SARS-Cov-2是一种单链RNA冠状病毒。通过与其他 病毒样品基因序列的比较，发现SARS-Cov-2与SARS-CoV(79.5％)[Nature,2020]和蝙蝠冠状病毒(96％)相似[bioRxiv,2020,2020.01.22.914952]，并推测该病毒可能起源于蝙蝠[bioRxiv,2020,2020.01.24.915157；Nature,2020]。SARS-Cov-2病毒属于βCoV，是区别于SARS-CoV和MERS-CoV的HCoV家族的第7个成员[New England Journal of Medicine,2020]，其余6个成员包括HCoV 229E、NL63、OC43、HKU1、SARS-CoV和MERS-CoV。
引起新型冠状病毒肺炎的是一种新型冠状病毒，它与人们熟知的引起非典型性肺炎的SARS-CoV同属冠状病毒，但类型不同，其致死率虽低于SARS-CoV但传染性远远高于SARS-CoV。全球传播表明新型冠状病毒肺炎疫情仍存在扩散的可能。但是到目前为止依旧没有任何特效药物能够治愈新型冠状病毒肺炎。开发有效的抗病毒药物和疫苗成为当下最为紧迫的任务。目前关于COVID-19的治疗主要依靠对症辅助治疗，尚缺乏有效的特效药物和疫苗。然而，新药开发和疫苗的制备是一项耗时的过程，不仅研发周期长，上市批准后的批量生产亦是一项耗时的工程。从上市药物中寻找具有抗SARS-Cov-2病毒感染作用的“老药”，是治疗和预防COVID-19这种爆发性感染疾病的一种有效策略。目前正在研究的抗SARS-Cov-2病毒药物主要包括RNA聚合酶抑制剂、β干扰素、单克隆抗体以及疫苗等。然而，到目前为止，尚无确切有效的抗病毒药物和疫苗。从对这些药物的体外抗病毒活性数据的分析来看，大多数药物的抗病毒IC
50处于低微摩尔至中微摩尔之间，体内疗效尚在观察之中。膦甲酸钠通过非竞争性抑制dNTPs而抑制病毒RNA聚合酶，逆转录酶，DNA聚合酶从而抑制病毒复制。膦甲酸钠能够有效治疗病毒感染疾病，如皮肤感染，疱疹性角膜炎，生殖器感染，或全身和大脑内的 感染。鉴于该药物的作用机制，本发明开展了膦甲酸钠在冠状病毒抗病毒药效的应用性研究。
开发有效的冠状病毒肺炎治疗特效药物成为了当下一个迫在眉睫需要解决的课题。在针对新型冠状病毒(SARS-Cov-2)病毒药物研发方面，本发明研究了膦甲酸钠对冠状病毒的抗病毒作用，膦甲酸钠可阻断新型冠状病毒感染宿主细胞，可用作治疗抗新冠肺炎新型冠状病毒感染方面的疾病治疗。
发明内容
本发明的目的在于提供膦甲酸钠在制备预防或治疗冠状病毒所致疾病的药物中的应用。
具体而言，为解决本发明的技术问题，采用如下技术方案：
本发明提供了膦甲酸钠或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药在制备预防和/或治疗冠状病毒所致疾病的药物中的应用。
在本发明的技术方案中，所述的冠状病毒为新型冠状病毒SARS-Cov-2、SARS-CoV、HCoV 229E、NL63、OC43、HKU1和MERS-CoV。
在本发明的技术方案中，冠状病毒所致疾病为SARS-Cov-2、SARS-CoV、HCoV 229E、NL63、OC43、HKU1或MERS-CoV任一病毒引起的感染性疾病或其并发症；优选为呼吸道感染疾病，例如，严重急性呼吸综合征、严重急性呼吸道综合征冠状病毒2型、中东呼吸综合症。
在本发明的技术方案中，膦甲酸钠如结构式(1)所示的
在本发明的技术方案中，膦甲酸钠或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药作为唯一活性成分在制备预防和/或治疗冠状病毒所致疾病的药物中的应用。
在本发明的技术方案中，膦甲酸钠或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药，与其他抗病毒药物制备的组合物作为活性成分在制备预防和/或治疗冠状病毒所致疾病的药物中的应用。
在本发明的技术方案中，其他抗病毒药物选自其他抗病毒药物选自更昔洛韦、阿昔洛韦、金刚烷胺、金刚乙胺、奥司他韦、阿巴卡韦、醋孟南、阿昔洛韦钠、阿德福韦、阿洛夫定、阿韦舒托、盐酸三环癸胺、阿拉诺丁、阿立酮、阿替韦啶甲磺酸酯、阿夫立定、西多福韦、西潘茶碱、恩曲他滨、盐酸阿糖胞苷、甲磺酸地拉韦啶、地昔洛韦、去羟肌苷、二噁沙利、依度尿苷、乙米韦林、依曲西他平、恩韦拉登、恩韦肟、贺普丁、泛昔洛韦、盐酸氯苯氢异喹、非西他滨、非阿尿苷、磷利酯、膦乙酸钠、甘西洛维钠、碘苷、茚地那韦、乙氧丁酮醛、拉米夫定、洛布卡韦、洛德腺苷、洛匹那韦、盐酸美莫汀、甲红硫脲、那非那韦、奈韦拉平、喷昔洛韦、吡罗达韦、利巴韦林、甲磺酸沙奎那韦、利托那韦、盐酸索金刚胺、索立夫定、匍枝青霉菌素、司他夫定、替诺福韦、盐酸梯络龙、曲氟尿苷、盐酸伐昔洛韦、阿糖腺苷、磷酸阿糖腺苷、阿糖腺苷磷酸钠、替拉那韦、韦罗肟、扎西他滨、齐多夫定、净韦肟。
本发明另一个方面提供了一种治疗或预防冠状病毒科病毒所致疾病的药物组合物，所述药物组合物中包含膦甲酸钠或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药。
在本发明的技术方案中，药物组合物的还包括药学上可接受的辅料。
在本发明的技术方案中，药物组合物的剂型为口服制剂、肺部吸入制剂、粘膜给药制剂、眼用制剂或注射剂。
在本发明的技术方案中，口服制剂选自颗粒剂、粉末剂、丸剂、片剂、胶囊或口服液。
本发明另一个方面提供了膦甲酸钠作为抗冠状病毒科病毒的消毒剂的用途。
本发明另一个方面提供了一种消除冠状病毒科病毒污染的消毒剂，所述消毒剂包括膦甲酸钠。
本发明另一个方面提供了一种用于治疗冠状病毒科病毒所致疾病的方法，包括将治疗有效量的膦甲酸钠或其药物学上可接受的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药给药于受试者。
本发明另一个方面提供了一种用于预防受试者感染冠状病毒科病毒的方法，包括将治疗有效量的膦甲酸钠或其药物学上可接受的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯或前药给药在感染前给予受试者。
在本发明的技术方案中，所述药物或药物组合物中不包含糖皮质激素或盐皮质激素。
本发明首次发现膦甲酸钠对新型冠状病毒有抗病毒作用，可阻断新型冠状病毒感染宿主细胞，可用作治疗抗冠肺病毒感染方面的疾病治疗。
膦甲酸钠抗新冠肺炎新型冠状病毒药效评价通过CCK8法对膦甲酸钠进行药效评价，对新冠肺炎新型冠状病毒(SARS-Cov-2)的半数有效浓度(EC
50)为0.89μM,，毒性低，具有一个良好的治疗窗口。
为了使本发明的上述目的、特征和优点能够更加明显易懂，下面结合附图对本发明的具体实施方式做详细的说明，但不能理解为对本发明的可实施范围的限定。
实施例1病毒扩增
将非洲绿猴肾细胞(VeroE6)按3×10
5个/孔，接种至96孔板中，在含有10％胎牛血清(FBS；GibcoInvitrogen)的minimum Eagle’smedium(MEM；GibcoInvitrogen)中，置37℃，5％CO
2培养，待长满单层。将新冠肺炎新型冠状病毒临床分离株100倍稀释接种到长满单层细胞的96孔板中，置37℃，5％CO
2培养两天(含正常对照组)。
两天后病变程度高达75％以上，置于-80℃超低温冰箱，反复冻融一次，收集细胞扩增的病毒液，3000r/min离心30分钟，去沉淀物，分装小管置-80℃超低温冰箱长期保存。
实施例2膦甲酸钠药物毒性评价
膦甲酸钠粉末用DMSO溶解后，加入培养液稀释至20mg/mL，DMSO终浓度为1％，经0.22μm滤膜过滤后置4℃保存；过滤后置4℃保存。按每孔约2.5×10
4细胞接种到96孔板，24～48h后待细胞长成单层后，弃去培养液，加入不同稀释度的药物l00μL/孔，正常细胞对照孔加入l00μL/孔MEM，37℃ 5％CO
2继续培养2～5天，每孔加CCK8法溶液(5mg/mL)20μL，置37℃ 5％CO
2保温箱中继续孵育4小时。吸弃培养上清液，每孔加l00μL二甲基亚砜(DMSO)，低速振荡10分钟，使结晶物充分融解。选择490nm波长，在酶联免疫监测仪上测定各孔光吸收值。通过毒性评价可知药物添加浓度达到400μM时，依然未见明显细胞毒性，说明药物的细胞毒性低，具有良好的治疗窗口。
实施例3膦甲酸钠抗新冠肺炎新型冠状病毒药效评价
为了评估药物的抗病毒效力，将VeroE6细胞在密度为5×10
4细胞/孔的48孔细胞培养皿中培养过夜。添加病毒(MOI为0.05)使其感染2小时。然后加入2倍梯度稀释的药物，每个浓度设置4个复孔，以200μM为药物起始浓度，在34℃、5％CO
2培养箱中孵育2天。记录细胞病变(Cytopathogenic Effect,CPE。细胞出现CPE按6级标准记录。记录CPE后，用CCK8法染色，进行OD值测定。用Reed—Muench法计算药物半数有效浓度(EC
50)，半数有效浓度(EC
50)为0.89μM。通过实验结果可知膦甲酸钠抗病毒的半数有效浓度低，抗病毒效果好。
实施例4免疫荧光检测
免疫荧光显微镜：为了检测VeroE6细胞中病毒蛋白的表达，将细胞用4％多聚甲醛固定并用0.5％TritonX-100透化。然后在室温下用5％牛血清白蛋白(BSA)封闭细胞2小时。将细胞与一抗(蝙蝠SARS相关冠状病毒的病毒核衣壳蛋白多克隆抗体，anti-NP，以1：1000稀释度)一起孵育2小时，然后与二抗孵育抗体(488AffiniPure Donkey Anti-Rabbit IgG(H+L)。细胞核用Hoechst33258染料(Beyotime,China)染色。通过荧光显微镜观察可知膦甲酸钠能有效杀灭细胞中的病毒，并且对细胞影响较小，具有良好的治疗窗口。
Claims (10)
- 膦甲酸钠或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药在制备预防和/或治疗冠状病毒所致疾病的药物中的应用。
- 根据权利要求1所述的用途，所述的冠状病毒为新型冠状病毒SARS-Cov-2、SARS-CoV、HCoV 229E、NL63、OC43、HKU1和MERS-CoV。
- 根据权利要求1所述的用途，冠状病毒所致疾病为SARS-Cov-2、SARS-CoV、HCoV 229E、NL63、HCoV-OC43、HKU1或MERS-CoV任一病毒引起的感染性疾病或其并发症；感染性疾病优选为呼吸道感染疾病。
- 根据权利要求1所述的用途，膦甲酸钠或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药作为唯一活性成分在制备预防和/或治疗冠状病毒所致疾病的药物中的应用；或者膦甲酸钠或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药，与其他抗病毒药物的组合物作为活性成分在制备预防和/或治疗冠状病毒所致疾病的药物中的应用；优选地，其他抗病毒药物选自更昔洛韦、阿昔洛韦、金刚烷胺、金刚乙胺、奥司他韦、阿巴卡韦、醋孟南、阿昔洛韦钠、阿德福韦、阿洛夫定、阿韦舒托、盐酸三环癸胺、阿拉诺丁、阿立酮、阿替韦啶甲磺酸酯、阿夫立定、西多福韦、西潘茶碱、恩曲他滨、盐酸阿糖胞苷、甲磺酸地拉韦啶、地昔洛韦、去羟肌苷、二噁沙利、依度尿苷、乙米韦林、依曲西他平、恩韦拉登、恩韦肟、贺普丁、泛昔洛韦、盐酸氯苯氢异喹、非西他滨、非阿尿苷、磷利酯、膦甲酸钠、膦乙酸钠、甘西洛维钠、碘苷、茚地那韦、乙氧丁酮醛、拉米夫定、洛布卡韦、洛德腺苷、洛匹那韦、盐酸美莫汀、甲红硫脲、那非那韦、奈韦拉平、喷昔洛韦、吡罗达韦、 利巴韦林、甲磺酸沙奎那韦、利托那韦、盐酸索金刚胺、索立夫定、匍枝青霉菌素、司他夫定、替诺福韦、盐酸梯络龙、曲氟尿苷、盐酸伐昔洛韦、阿糖腺苷、磷酸阿糖腺苷、阿糖腺苷磷酸钠、替拉那韦、韦罗肟、扎西他滨、齐多夫定、净韦肟。
- 一种治疗或预防冠状病毒所致疾病的药物组合物，所述药物组合物中包含膦甲酸钠或其可药用的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药；优选地，所述药物组合物中不包含糖皮质激素或盐皮质激素。
- 根据权利要求5所述的药物组合物，药物组合物的还包括药学上可接受的辅料。
- 根据权利要求5所述的药物组合物，药物组合物的剂型为口服制剂、肺部吸入制剂、粘膜给药制剂、眼用制剂或注射剂；优选地，口服制剂选自颗粒剂、粉末剂、丸剂、片剂、胶囊或口服液。
- 一种消除冠状病毒科病毒污染的消毒剂，所述消毒剂包括膦甲酸钠。
- 一种用于治疗或预防冠状病毒科病毒所致疾病的方法，包括将治疗有效量的膦甲酸钠或其药物学上可接受的盐、同位素、立体异构体、立体异构体的混合物、互变异构体、酯、酰胺或前药给药于受试者。
- 根据权利要求5-7任一项所述的药物组合物或权利要求8所述的消毒剂或权利要求9所述的方法，其中冠状病毒为新型冠状病毒SARS-Cov-2、SARS-CoV、HCoV 229E、NL63、OC43、HKU1和MERS-CoV。
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