WO2021170093A1 - 双硫仑在抗冠状病毒中的应用 - Google Patents

双硫仑在抗冠状病毒中的应用 Download PDF

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WO2021170093A1
WO2021170093A1 PCT/CN2021/078185 CN2021078185W WO2021170093A1 WO 2021170093 A1 WO2021170093 A1 WO 2021170093A1 CN 2021078185 W CN2021078185 W CN 2021078185W WO 2021170093 A1 WO2021170093 A1 WO 2021170093A1
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coronavirus
disulfiram
application according
hcov
application
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杨海涛
靳振明
杨秀娜
赵耀
饶子和
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上海科技大学
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Priority to US17/801,689 priority Critical patent/US20230293457A1/en
Priority to CN202180016668.3A priority patent/CN115175673A/zh
Priority to JP2022551788A priority patent/JP2023515227A/ja
Priority to KR1020227033090A priority patent/KR20220146558A/ko
Priority to EP21760398.4A priority patent/EP4115880A4/en
Priority to BR112022017060A priority patent/BR112022017060A2/pt
Publication of WO2021170093A1 publication Critical patent/WO2021170093A1/zh

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • 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

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  • the invention belongs to the technical field of biomedicine, and relates to the application of disulfiram in the anti-coronavirus, and in particular to the application of disulfiram in the preparation of medicines for treating and/or preventing diseases caused by the coronavirus.
  • Coronavirus is a type of virus closely related to humans and animals. Coronavirus HCoV-229E and HCoV-OC43 can cause the common cold (van der Hoek, L., Pyrc, K., Jebbink, M. et al. Identification of a new human coronavirus. Nat Med 2004, 10, 368-373).
  • the severe acute respiratory syndrome (SARS) caused by the SARS coronavirus between 2002 and 2003 infected 8,098 people worldwide (Stadler, K., Massignani, V., Eickmann, M. et al. SARS--beginning to understand a new virus. Nat Rev Microbiol 2003, 1,209–218).
  • the HCoV-NL63 identified in 2004 can also cause cold-like respiratory diseases (van der Hoek, L., Pyrc, K., Jebbink, M. et al. Identification of a new human coronavirus. Nat Med 2004, 10, 368-373 ).
  • the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) appeared in 2012. As of April 26, 2016, it has caused 1,728 infections in 27 countries (de Wit, E., van Doremalen, N., Falzarano, D. et al. .SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol 2016, 14, 523–534.).
  • the recently circulating SARS-CoV-2 virus can cause COVID-19, and the clinical manifestations are fever, dry cough and dyspnea (Jeannette Guarner, MD, Three Emerging Coronaviruses in Two Decades: The Story of SARS, MERS, and Now COVID-19, American Journal of Clinical Pathology,,aqaa029).
  • Coronavirus has a huge impact on the livestock industry: Porcine Epidemic Diarrhea Virus (PEDV), Gastroenteritis Virus (TGEV) and Porcine Delta Coronavirus (PDCoV, also called Delta Virus), which can cause severe enteritis in pigs, Diarrhea, vomiting and dehydration have brought huge losses to the pig industry (Akimkin V, Beer M, Blome S, et al. New Chimeric Porcine Coronavirus in Swine Feces, Germany, 2012. Emerge Infect Dis. 2016, 22(7) :1314–1315).
  • Feline infectious peritonitis virus FIPV
  • IBV Avian infectious bronchitis virus
  • IBV infects poultry and is a widespread poultry disease that has a huge negative impact on the poultry industry.
  • Coronaviruses are systematically classified as Nidovirales (Coronaviridae), Coronaviridae (Coronaviridae), Coronavirus subfamily (Orthocoronavirinae).
  • the sequence of the SARS-CoV-2 coronavirus genome has been announced a few days ago. This sequence is identical to the nucleoside of SARS-Cov. The acid similarity is about 90%, and the protein sequence has about 80% sequence similarity with SARS-CoV.
  • the genome of the coronavirus is a single-stranded positive-stranded RNA with a length of about 28 kb, which mainly encodes structural proteins required for virus packaging and non-structural proteins related to replication and transcription.
  • the development of drugs and vaccines for the treatment of coronavirus-related diseases mainly targets the above two types of proteins.
  • Two-thirds of the genes in the viral genome mainly encode non-structural proteins.
  • the virus encodes two polymerase proteins, pp1a and pp1ab, which are used to participate in the replication process of the virus.
  • pp1a and pp1ab can be cleaved into 16 non-structural proteins nsp1-16 through two virus-encoded papains and main protease. Only when these functional subunits are cleaved into independent protein units by the virus-encoded protease , The virus can complete the normal transcription and replication functions, and then assemble into a replication transcription complex to complete the replication and transcription of the virus.
  • papain has 3 restriction sites; the main protease has 11 restriction sites on pp1a and pp1ab. It can be seen that the main protease plays a key regulatory role in the process of virus transcription and replication, so it has become the focus of research (Ziebuhr, J.; Snijder, EJ; Gorbalenya, AEVirus-encoded proteinases and proteolytic processing in the Nidovirales. J Gen Virol 2000 ,81,853-79.; Ziebuhr, J. Molecular biology of severe acute respiratory syndrome coronavirus. Curr Opin Microbiol 2004, 7,412-9.). Due to the importance of the main protease for the amplification and replication of coronaviruses, it is particularly important to find inhibitors that are specific to the main protease catalytic site and have high safety for drug development.
  • Disulfiram (Disulfiram; CAS number: 97-77-8) is a specific acetaldehyde dehydrogenase (ALDH1) inhibitor (Liu, Xinwei, et al. "Targeting ALDH1A1 by disulfiram/copper complex inhibitors non-small) cell lung cancer recurrence driven by ALDH-positive cancer stem cells. "Oncotarget 7.36(2016):58516.), used for the treatment of chronic alcoholism, acute sensitivity to alcohol. Disulfiram also acts on the dopaminergic system. Disulfiram and its metabolite carbon disulfide can inhibit dopamine-hydroxylase (DBH) and increase dopamine levels.
  • DBH dopamine-hydroxylase
  • dithion can also inhibit dopamine-hydroxylase, leading to an increase in the concentration of dopamine in the brain and a decrease in norepinephrine, which may imply the anti-addiction effect of dithion in alcohol dependence.
  • Disulfiram can be metabolized into a small molecule in the body, thereby promoting the coagulation of the natural protein NPL4 and binding to its partner p97 enzyme. This process will inhibit the NPL4-p97 complex that promotes tumor growth and induce cancer cell death.
  • Disulfiram has also been found to have specific activity on zinc finger and ring finger ubiquitin E3 ligases.
  • the technical problem to be solved by the present invention is to provide the application of disulfiram in the anti-coronavirus in view of the defect that there is no effective treatment and/or prevention of the disease caused by the coronavirus in the prior art, and specifically relates to the application of disulfiram in the anti-coronavirus Application in the preparation of medicines for the treatment and/or prevention of diseases caused by coronaviruses.
  • the present invention mainly solves the above technical problems through the following technical solutions.
  • the present invention provides the application of disulfiram (CAS number: 97-77-8) in the preparation of medicines for treating and/or preventing diseases caused by coronaviruses.
  • the disease is a mammalian or avian disease.
  • the mammals include humans, pigs and cats.
  • coronavirus described in the present invention is well-known in the art, and belongs to the subfamily Orthocoronavirinae in the order Nidovirales, Coronaviridae, and Coronaviridae.
  • Coronaviruses are RNA viruses with an envelope and a single-stranded positive-stranded genome. They are a large group of viruses that are widespread in nature.
  • the purpose of the present invention is to provide a potential treatment plan for diseases caused by coronavirus infection.
  • the coronavirus of the present invention preferably belongs to the orthocoronavirus subfamily (Orthocoronavirinae), and more preferably belongs to the genus Alphacoronavirus, Betacoronavirus, Gammacoronavirus, or Deltacoronavirus.
  • the disulfiram can be used to treat diseases caused by SARS-CoV-2 (Beta coronavirus), and should also be used to treat other coronaviruses SARS-CoV (Beta coronavirus).
  • HCoV-HKU1 Human coronavirus HKU1; Beta coronavirus genus
  • HCoV-NL63 Human coronavirus NL63; Alpha coronavirus genus
  • HCoV -OC43 Humancoronavirus OC43
  • HCoV-229E Humancoronavirus 22E; Alphacoronavirus
  • TGEV transmissible gastroenteritis virus
  • PEDV Porcine Epidemic Diarrhea Virus
  • PEDV Alpha Coronavirus
  • PDCoV Porcine Delta Coronavirus
  • Feline Infectious Peritonitis virus, FIPV Alpha coronavirus genus
  • Alpha coronavirus genus avian infectious bronchitis virus
  • IBV Infectious bronchitis virus
  • Gamma coronavirus genus avian infectious bronchitis virus
  • the coronavirus of the present invention is preferably selected from SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-HKU1, HCoV-NL63, HCoV-OC43, HCoV-229E, TGEV, PEDV, PDCoV, FIPV or IBV.
  • the disulfiram or its pharmaceutically acceptable salt of the present invention is in the form of a pharmaceutical composition containing it; preferably, the pharmaceutical composition is disulfiram and/or its pharmaceutically acceptable salt.
  • An acceptable salt is used as the only active ingredient of the pharmaceutical composition; and/or, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, such as a pharmaceutically acceptable pharmaceutical excipient.
  • the disulfiram or a pharmaceutically acceptable salt thereof of the present invention is in the form of a kit containing it, and the kit also includes drugs and/or drugs for treating coronavirus-related diseases Drugs to treat diseases caused by other viruses.
  • the pharmaceutical composition of the present invention with disulfiram as the active ingredient can be prepared according to methods well known in the art.
  • the compound of the present invention can be formulated into any dosage form suitable for human or animal use.
  • the weight content of the compound of the present invention in its pharmaceutical composition is usually 0.1-99.0%.
  • the pharmaceutically acceptable carrier may be a conventional carrier in the art, and the carrier may be any suitable physiologically or pharmaceutically acceptable pharmaceutical excipient.
  • the pharmaceutical excipients are conventional pharmaceutical excipients in the field, and preferably include pharmaceutically acceptable excipients, fillers or diluents. More preferably, the pharmaceutical composition comprises 0.01-99.99% of the above-mentioned protein and/or the above-mentioned antibody drug conjugate, and 0.01-99.99% of the pharmaceutical carrier, and the percentage is based on the percentage of the pharmaceutical composition. The mass percentage.
  • the disulfiram or the pharmaceutical composition containing it in the present invention can be administered in a unit dosage form, and the route of administration can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous injection, nasal cavity, oral mucosa, eye , Lungs and respiratory tract, skin, vagina, rectum, etc.
  • the dosage form for administration may be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops
  • the solid dosage form can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.
  • the disulfiram in the present invention can be made into ordinary preparations, and can also be made into slow-release preparations, controlled-release preparations, targeted preparations and various particle delivery systems.
  • pharmaceutically acceptable means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for use by patients.
  • the "patient” is preferably a mammal, more preferably a human.
  • pharmaceutically acceptable salt refers to the salt prepared by disulfiram and a relatively non-toxic, pharmaceutically acceptable acid or base in the present invention.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the present invention finds through the in vitro enzyme activity experiment that disulfiram can well inhibit the activity of the main protease in the coronavirus, and fills in the deficiency of the prior art for the lack of treatment of diseases caused by the coronavirus.
  • the disulfiram can be further studied and modified for application.
  • Figure 1 The inhibitory activity of disulfiram on the main protease of the new coronavirus; 1: DMSO (negative control), 2: compound molecule; 3: positive control (N3 inhibitor).
  • Figure 2 Inhibition curve of disulfiram on the main protease of the new coronavirus.
  • Figure 3 The inhibitory activity of disulfiram on the new coronavirus at the cellular level.
  • Enzyme activity experiment fluorescent substrate MCA-AVLQSGFR-Lys(Dnp)-Lys-NH 2 , the excitation wavelength and emission wavelength of this fluorescent substrate are 320nm and 405nm, respectively.
  • Enzyme activity reaction buffer is 50mM Tris-HCl (pH 7.3), 1mM EDTA; Enzyme activity reaction temperature: 30°C.
  • the reaction is started by adding protease, the final concentration of the protease reaction is 0.2 ⁇ M, the substrate concentration is 20 ⁇ M, and the disulfiram concentration is 1.5 ⁇ M (Xue X, Yang H, Shen W, et al. Production of authentic SARS-CoV Mpro with enhanced activity :application as a novel tag-cleavage endopeptidase for protein overproduction[J].Journal of molecular biology,2007,366(3):965-975.).
  • the positive control used was an N3 inhibitor, which is known to effectively inactivate the main proteases of the coronavirus (Yang Haitao, Xie Weiqing, Xiaoyu X, et al. Design of wide-spectrum inhibitors targeting coronavirus main proteases [J]. Life Organic Chemistry, 2005 ,3(10):1742-1752.), the structural formula is as follows:
  • the fluorescent substrate used in the determination of enzyme activity inhibition curve MCA-AVLQSGFR-Lys(Dnp)-Lys-NH 2 , the excitation wavelength and emission wavelength of this fluorescent substrate are 320nm and 405nm, respectively.
  • Enzyme activity inhibition curve determination buffer is 50mM Tris-HCl (pH 7.3), 1mM EDTA; reaction temperature: 30°C.
  • the reaction was started by adding protease, the final concentration of the protease reaction was 0.2 ⁇ M, the substrate concentration was 20 ⁇ M, and 11 different concentrations of disulfiram were used to measure the IC 50 value of 9.35 ⁇ M ( Figure 2) (Jin Z, Du X,Xu Y,et al.Structure of Mpro from COVID-19 virus and discovery of its inhibitors[J].Nature,2020,582(7811):1-9.).
  • the in vitro cell antiviral experiment adopts qRT-PCR method to detect. Approximately Vero cells were seeded in a 96-well plate, incubated at 37°C for 20-24 hours, and then treated with 10 ⁇ M disulfiram for 1 hour. Subsequently, SARS-CoV-2 was added to infect the cells for two hours, and the MOI (multiplicity of infection) was 0.01. The virus and drug mixture are then removed, and the cells are further cultured with a fresh medium containing drugs after washing.
  • disulfiram can inhibit the replication of the new coronavirus, so disulfiram can be used to treat related diseases caused by coronavirus ( Figure 3).

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Abstract

双硫仑在抗冠状病毒中的应用。双硫仑在制备治疗和/或预防冠状病毒引发的疾病的药物中的应用。通过体外酶活实验发现双硫仑可以很好地抑制冠状病毒中的主蛋白酶的活性，填补了现有技术缺乏治疗冠状病毒引发的疾病的不足。

Description

双硫仑在抗冠状病毒中的应用
本申请要求申请日为2020/2/26的中国专利申请2020101216884的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于生物医药技术领域，涉及双硫仑在抗冠状病毒中的应用，具体涉及双硫仑在制备治疗和/或预防冠状病毒引发的疾病的药物中的应用。
背景技术
冠状病毒是一类与人畜密切相关的病毒。冠状病毒HCoV-229E和HCoV-OC43会引起普通感冒(van der Hoek,L.,Pyrc,K.,Jebbink,M.et al.Identification of a new human coronavirus.Nat Med 2004,10,368–373)。2002至2003年期间由SARS冠状病毒引起的严重急性呼吸系统综合征(SARS)在全球造成8098人感染(Stadler,K.,Masignani,V.,Eickmann,M.et al.SARS—beginning to understand a new virus.Nat Rev Microbiol 2003,1,209–218)。2004年鉴定出的HCoV-NL63同样能引起类似感冒的呼吸道疾病(van der Hoek,L.,Pyrc,K.,Jebbink,M.et al.Identification of a new human coronavirus.Nat Med 2004,10,368–373)。2012年出现了中东呼吸综合征冠状病毒(MERS-CoV)，截至2016年4月26日，在27国造成1,728例感染(de Wit,E.,van Doremalen,N.,Falzarano,D.et al.SARS and MERS:recent insights into emerging coronaviruses.Nat Rev Microbiol 2016,14,523–534.)。最近流行的SARS-CoV-2病毒会引发COVID-19，临床表现为发烧，干咳和呼吸困难(Jeannette Guarner,MD,Three Emerging Coronaviruses in Two Decades:The Story of SARS,MERS,and Now COVID-19,American Journal of Clinical Pathology,,aqaa029)。冠状病毒对于畜牧业影响巨大：猪流行性腹泻病毒 (PEDV)、肠胃炎病毒(TGEV)和猪丁型冠状病毒(Porcine delta coronavirus，PDCoV，也叫德尔塔病毒)，可引起猪的严重肠炎、腹泻、呕吐和脱水，给养猪业带来巨大的损失(Akimkin V,Beer M,Blome S,et al.New Chimeric Porcine Coronavirus in Swine Feces,Germany,2012.Emerg Infect Dis.2016,22(7):1314–1315)。猫传染性腹膜炎病毒(FIPV)可引起的猫科动物的致死性疾病。禽传染性支气管炎病毒(IBV)感染禽类，是一种分布广泛的家禽疾病，对家禽业造成了巨大的负面影响。
冠状病毒在系统分类上属套式病毒目(Nidovirales)冠状病毒科(Coronaviridae)冠状病毒亚科(Orthocoronavirinae)，日前SARS-CoV-2冠状病毒基因组序列已经公布，该序列与SARS-Cov的核苷酸相似度约为90％，蛋白质序列与SARS-CoV有约80％的序列相似性。冠状病毒的基因组为单股正链RNA，长度约28kb，主要编码病毒包装所需的结构蛋白以及与复制转录相关的非结构蛋白。开发治疗冠状病毒相关疾病的药物和疫苗主要针对上述两类蛋白。病毒基因组的三分之二的基因主要编码非结构蛋白。病毒编码了两种多聚酶蛋白pp1a和pp1ab，用于参与病毒的复制过程。pp1a和pp1ab通过两种由病毒编码的木瓜蛋白酶和主蛋白酶(main protease)可以将其切割成16个非结构蛋白nsp1-16，只有当这些功能亚基被病毒编码的蛋白酶切割成独立的蛋白单元，病毒才能完成正常的转录、复制功能，进而组装成复制转录复合物，完成病毒的复制和转录。其中，木瓜蛋白酶有3个酶切位点；主蛋白酶在pp1a和pp1ab上存在11个酶切位点。可见主蛋白酶在病毒的转录、复制过程中发挥关键的调节作用，因此成为研究的焦点(Ziebuhr,J.；Snijder,E.J.；Gorbalenya,A.E.Virus-encoded proteinases and proteolytic processing in the Nidovirales.J Gen Virol 2000,81,853-79.；Ziebuhr,J.Molecular biology of severe acute respiratory syndrome coronavirus.Curr Opin Microbiol 2004,7,412-9.)。由于主蛋白酶对冠状病毒扩增复制的重要性，因此寻找针对主蛋白酶催化位点专一性强、安全性高的抑制剂对于药物开发 显得尤其重要。
双硫仑(Disulfiram；CAS号：97-77-8)是一个特异性的乙醛脱氢酶(ALDH1)抑制剂(Liu,Xinwei,et al."Targeting ALDH1A1 by disulfiram/copper complex inhibits non-small cell lung cancer recurrence driven by ALDH-positive cancer stem cells."Oncotarget 7.36(2016):58516.)，用于治疗慢性酒精中毒，对酒精产生急性敏感性。双硫仑还作用于多巴胺能系统，双硫仑及其代谢物二硫化碳均可抑制多巴胺-羟化酶(DBH)，使多巴胺水平升高。这可能会导致一些神经精神症状，如谵妄、偏执、记忆障碍、共济失调、构音障碍和额叶释放信号。除了这种作用，双硫磷还可以抑制多巴胺-羟化酶，导致大脑中多巴胺浓度升高，去甲肾上腺素下降，这可能暗示了双硫磷在酒精依赖中的抗瘾作用。
2017年自然科学杂志(Skrott,Zdenek,et al."Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4."Nature 552.7684(2017):194-199.]),发表了其抗肿瘤活性，研究发现Disulfiram在体内能被代谢成为一种小分子，从而促进天然蛋白NPL4凝结并与其配偶体p97酶类结合，这个过程就会抑制促进肿瘤生长的NPL4-p97复合体发挥作用，进而诱发癌细胞死亡。此外，Disulfiram还被发现对锌指和环指泛素E3连接酶具有特异性活性，这些连接酶在癌症的发展中起着重要的作用(R Kona,F.,D.A.M.B.Buac,and A.M Burger."Disulfiram,and disulfiram derivatives as novel potential anticancer drugs targeting the ubiquitin proteasome system in both preclinical and clinical studies."Current cancer drug targets 11.3(2011):338-346.)。相关专利申请为WO2017077336A1。
现有技术中尚无以上双硫仑可用于治疗冠状病毒引发的相关疾病。
发明内容
本发明所要解决的技术问题是针对现有技术中尚无有效治疗和/或预防 冠状病毒所引发的疾病的药物的缺陷，提供双硫仑在抗冠状病毒中的应用，具体涉及双硫仑在制备治疗和/或预防冠状病毒引发的疾病的药物中的应用。
本发明主要通过以下技术方案解决上述技术问题。
本发明提供双硫仑(CAS号：97-77-8)在制备治疗和/或预防冠状病毒引发的疾病的药物中的应用。
较佳地，所述的疾病为哺乳动物或者禽类疾病。
较佳地，所述的哺乳动物包括人、猪和猫。
本发明所述的冠状病毒，其定义为本领域熟知，在系统分类上属套式病毒目(Nidovirales)冠状病毒科(Coronaviridae)冠状病毒亚科(Orthocoronavirinae)。冠状病毒是具有囊膜(envelope)、基因组为单股正链的RNA病毒，是自然界广泛存在的一大类病毒。
本发明的目的是提供冠状病毒感染引起的疾病的潜在治疗方案。本发明所述的冠状病毒较佳地属于正冠状病毒亚科(Orthocoronavirinae)，更佳地属于Alpha冠状病毒属、Beta冠状病毒属、Gamma冠状病毒属或者Delta冠状病毒属。
在本发明一较佳实施例中，所述的双硫仑除可用于治疗SARS-CoV-2(Beta冠状病毒属)引发的疾病以外，还应可治疗其他冠状病毒SARS-CoV(Beta冠状病毒属)和MERS-CoV等引起的重大传染病，亦可作为普通感冒药，治疗HCoV-HKU1(Human coronavirus HKU1；Beta冠状病毒属)、HCoV-NL63(Human coronavirus NL63；Alpha冠状病毒属)、HCoV-OC43(Human coronavirus OC43)以及HCoV-229E(Human coronavirus 22E；Alpha冠状病毒属)等冠状病毒引起的疾病；还可作为兽药，治疗猪传染性胃肠炎病毒(Transmissible gastroenteritis virus,TGEV；Alpha冠状病毒属)、猪流行性腹泻病毒(Porcine epidemic diarrhea virus,PEDV；Alpha冠状病毒属)、猪丁型冠状病毒(Porcine delta coronavirus，PDCoV；Delta冠状病毒属)、猫传染性腹膜炎病毒(Feline infectious peritonitis virus,FIPV；Alpha冠状病毒 属)、禽传染性支气管炎病毒(Infectious bronchitis virus,IBV；Gamma冠状病毒属)等动物疾病。
因此，本发明所述冠状病毒的较佳地选自SARS-CoV-2、SARS-CoV、MERS-CoV、HCoV-HKU1、HCoV-NL63、HCoV-OC43、HCoV-229E、TGEV、PEDV、PDCoV、FIPV或者IBV。
在某一方案中，本发明的双硫仑或其药学上可接受的盐以包含其的药物组合物的形式存在；较佳地，所述药物组合物以双硫仑和/或其药学上可接受的盐作为所述药物组合物的唯一活性成份；和/或，所述药物组合物还包含药学上可接受的载体，例如药学上可接受的药用辅料。
在某一方案中，本发明的双硫仑或其药学上可接受的盐以包含其的套装药盒的形式存在，所述套装药盒还包括治疗与冠状病毒相关的疾病的药物和/或治疗其他病毒引起的疾病的药物。
本发明中涉及的以双硫仑作为活性成份的药物组合物，均可根据本领域公知的方法制备。可通过将本发明化合物制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的重量含量通常为0.1-99.0％。
所述的药学可接受的载体可为本领域常规的载体，所述的载体可以为任意合适的生理学或药学上可接受的药物辅料。所述的药物辅料为本领域常规的药物辅料，较佳地包括药学上可接受的赋形剂、填充剂或稀释剂等。更佳地，所述的药物组合物包括0.01～99.99％的上述蛋白质和/或上述的抗体药物偶联物，和0.01～99.99％的药用载体，所述百分比为占所述药物组合物的质量百分比。
本发明中双硫仑或含其的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬 剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明中的双硫仑可以制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
术语“药学上可接受的”是指盐、溶剂、辅料等一般无毒、安全，并且适合于患者使用。所述的“患者”优选哺乳动物，更优选为人类。
术语“药学上可接受的盐”是指本发明中双硫仑与相对无毒的、药学上可接受的酸或碱制备得到的盐。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：
本发明通过体外酶活实验发现双硫仑可以很好地抑制冠状病毒中的主蛋白酶的活性，填补了现有技术缺乏治疗冠状病毒引发的疾病的不足。可对双硫仑进行进一步研究、改造以进行应用。
附图说明
图1：双硫仑对新型冠状病毒主蛋白酶的抑制活性；1：DMSO(阴性对照),2:化合物分子；3：阳性对照(N3抑制剂)。
图2：双硫仑对新型冠状病毒主蛋白酶的抑制曲线。
图3：双硫仑在细胞水平上对新冠病毒的抑制活性。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1
从不同的化合物库中进行高通量筛选，成功筛选的双硫仑对新型冠状病毒主蛋白酶均有较好的抑制效果。酶活实验条件具体为：
酶活实验荧光底物：MCA-AVLQSGFR-Lys(Dnp)-Lys-NH 2，此荧光底物的激发波长和发射波长分别为320nm和405nm。
酶活反应buffer为50mM Tris–HCl(pH 7.3)，1mM EDTA；酶活反应温度：30℃。反应起始通过添加蛋白酶，蛋白酶反应终浓度为0.2μM，底物浓度为20μM，双硫仑浓度1.5μM(Xue X,Yang H,Shen W,et al.Production of authentic SARS-CoV Mpro with enhanced activity:application as a novel tag-cleavage endopeptidase for protein overproduction[J].Journal of molecular biology,2007,366(3):965-975.)。
所用阳性对照为N3抑制剂，已知其能够有效灭活冠状病毒主蛋白酶(杨海涛,谢卫青,Xiaoyu X,et al.Design of wide-spectrum inhibitors targeting coronavirus main proteases[J].生命有机化学,2005,3(10):1742-1752.)，结构式如下所示：
Figure PCTCN2021078185-appb-000001
根据图1可知：双硫仑的酶活实验曲线，明显区别于阴性对照，对冠状病毒主蛋白酶有明显抑制活性。
实施例2
酶活抑制曲线测定使用的荧光底物：MCA-AVLQSGFR-Lys(Dnp)-Lys-NH 2，此荧光底物的激发波长和发射波长分别为320nm和405nm。
酶活抑制曲线测定buffer为50mM Tris–HCl(pH 7.3)，1mM EDTA；反应温度：30℃。反应起始通过添加蛋白酶，蛋白酶反应终浓度为0.2μM，底物浓度为20μM，使用11个不同浓度的双硫仑进行测量，测试结果显示IC 50值为9.35μM(图2)(Jin Z,Du X,Xu Y,et al.Structure of Mpro from COVID-19 virus and discovery of its inhibitors[J].Nature,2020,582(7811):1-9.)。
实施例3
体外细胞抗病毒实验采用qRT-PCR的方法检测。将约Vero细胞接种于96孔板，37℃孵育20-24h后使用10μM的双硫仑处理细胞1h。随后加入SARS-CoV-2感染细胞两小时，MOI(multiplicity of infection)为0.01。然后去除病毒和药物混合物，清洗后用含药的新鲜培养基进一步培养细胞。经过72小时培养后使用QIAamp viral RNA mini kit(Qiagen)从培养上清液中提取病毒RNA，最后用qRT-PCR检测(Jin Z,Du X,Xu Y,et al.Structure of Mpro from COVID-19 virus and discovery of its inhibitors[J].Nature,2020,582(7811):1-9.)。
通过体外细胞抗病毒实验，发现双硫仑可抑制新型冠状病毒复制，因此双硫仑可用于治疗冠状病毒引发的相关疾病(图3)。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (9)

  1. 双硫仑在制备治疗和/或预防冠状病毒引发的疾病的药物中的应用。
  2. 如权利要求1所述的应用，其特征在于，所述的疾病为哺乳动物或者禽类疾病。
  3. 如权利要求2所述的应用，其特征在于，所述的哺乳动物包括人、猪和猫。
  4. 如权利要求1所述的应用，其特征在于，所述的冠状病毒属于正冠状病毒亚科(Orthocoronavirinae)。
  5. 如权利要求4所述的应用，其特征在于，所述的冠状病毒属于Alpha冠状病毒属、Beta冠状病毒属、Gamma冠状病毒属或者Delta冠状病毒属。
  6. 如权利要求5所述的应用，其特征在于，所述的冠状病毒选自SARS-CoV-2、SARS-CoV、MERS-CoV、HCoV-HKU1、HCoV-NL63、HCoV-OC43、HCoV-229E、TGEV、PEDV、PDCoV、FIPV或者IBV。
  7. 如权利要求1所述的应用，其特征在于，所述双硫仑作为所述药物组合物的唯一活性成分。
  8. 如权利要求7所述的应用，其特征在于，所述的药物组合物还包含药学上可接受的载体，例如药学上可接受的药用辅料。
  9. 如权利要求1～8任一项所述的应用，其特征在于，所述双硫仑以包含其的套装药盒的形式存在，所述套装药盒还包括治疗与冠状病毒相关的疾病的药物和/或治疗其他病毒引起的疾病的药物。
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