冠状病毒及其治疗药物研究进展

李鹤, 谭晓川, 姜栋, 唐柔, 郝玉梅, 张宇佳, 方夏琴, 马春晓, 李平平, 郑稳生

中国药学杂志 ›› 2020, Vol. 55 ›› Issue (4) : 284-292.

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中国药学杂志 ›› 2020, Vol. 55 ›› Issue (4) : 284-292. DOI: 10.11669/cpj.2020.04.004
新冠肺炎疫情防控

冠状病毒及其治疗药物研究进展

  • 李鹤, 谭晓川, 姜栋, 唐柔, 郝玉梅, 张宇佳, 方夏琴, 马春晓, 李平平, 郑稳生*
作者信息 +

Research Progress in Coronavirus and its Therapeutic Drugs

  • LI He, TAN Xiao-chuan, JIANG Dong, TANG Rou, HAO Yu-mei, ZHANG Yu-jia, FANG Xia-qin, MA Chun-xiao, LI Pin-pin, ZHENG Wen-sheng*
Author information +
文章历史 +

摘要

2019年底开始,中国武汉出现了由严重急性呼吸综合冠状病毒2(severs acute respiratory syndrome coronavirus 2,SARS-CoV-2)引发的2019冠状病毒病(corona virus disease 2019,COVID-19),并迅速蔓延。此前世界范围内已爆发过两次不同冠状病毒引发的导致严重后果的疫情,分别是严重急性呼吸系统综合征冠状病毒(severe acute respiratory syndrome coronavirus,SARS-CoV)和中东呼吸系统综合征冠状病毒(middle east respiratory syndrome coronavirus,MERS-CoV)。本文介绍了冠状病毒的结构与分类,讨论了3种冠状病毒——SARS-CoV、MERS-CoV和SARS-CoV-2的起源、病毒学特点与流行病学概述,综述了目前上市以及研发中可能预防和治疗冠状病毒感染的药物,以期阐释冠状病毒的特征,为SARS-CoV-2及新型冠状病毒的防治提供参考。

Abstract

Beginning at the end of 2019, corona virus disease 2019(COVID-19) caused by sevare acute respiratory syndrome coronavirus(SARS-CoV-2) appeared in Wuhan, China, and spread rapidly across the country. Prior to this, there had been two outbreaks in the world that caused serious consequences by different coronaviruses: severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). This article introduces the structure and classification of coronaviruses, discusses the origin, virological characteristics, and epidemiological overview of three coronaviruses-SARS-CoV, MERS-CoV, and SARS-CoV-2, and reviews the drugs that are currently on the market and are being developed to treat coronavirus infections, in order to explain the characteristics of coronavirus and provide new ideas for the prevention and control of 2019-nCoV and new coronavirus.

关键词

冠状病毒 / 2019冠状病毒病 / 严重急性呼吸综合冠状病毒2 / 严重急性呼吸系统综合征冠状病毒 / 中东呼吸系统综合征冠状病毒 / 治疗药物

Key words

coronavirus / COVID-19 / SARS-CoV-2 / SARS-CoV / MERS-CoV / therapeutic drug

引用本文

导出引用
李鹤, 谭晓川, 姜栋, 唐柔, 郝玉梅, 张宇佳, 方夏琴, 马春晓, 李平平, 郑稳生. 冠状病毒及其治疗药物研究进展[J]. 中国药学杂志, 2020, 55(4): 284-292 https://doi.org/10.11669/cpj.2020.04.004
LI He, TAN Xiao-chuan, JIANG Dong, TANG Rou, HAO Yu-mei, ZHANG Yu-jia, FANG Xia-qin, MA Chun-xiao, LI Pin-pin, ZHENG Wen-sheng. Research Progress in Coronavirus and its Therapeutic Drugs[J]. Chinese Pharmaceutical Journal, 2020, 55(4): 284-292 https://doi.org/10.11669/cpj.2020.04.004
中图分类号: R97   

参考文献

[1] CHAN J F W, YUAN S, KOK K H, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person to person transmission: a study of a family cluster [J]. The Lancet, 2020. https://doi.org/10.1016/S0140-6736(20)30154-9.
[2] THE L. Emerging understandings of 2019-nCoV [J]. The Lancet, 2020, 395(10221). https://doi.org/10.1016/S0140-6736(20)30186-0.
[3] WU J T, LEUNG K, LEUNG G M. Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study [J]. The Lancet, 2020. https://doi.org/10.1016/S0140-6736(20)30260-9.
[4] DE WIT E, VAN DOREMALEN N, FALZARANO D, et al. SARS and MERS: recent insights into emerging coronaviruses [J]. Nat Rev Microbiol, 2016, 14(8):523-534.
[5] SU S, WONG G, SHI W, et al. Epidemiology, Genetic Recombination, and Pathogenesis of Coronaviruses [J]. Trends Microbiol, 2016, 24(6):490-502.
[6] FORNI D, CAGLIANI R, CLERICI M, et al. Molecular Evolution of Human Coronavirus Genomes [J]. Trends Microbiol, 2017, 25(1):35-48.
[7] BRIAN D A, BARIC R S. Coronavirus genome structure and replication [J]. Curr Top Microbiol Immunol, 2005, 287:1-30.
[8] BARCENA M, OOSTERGETEL G T, BARTELINK W, et al. Cryo-electron tomography of mouse hepatitis virus: Insights into the structure of the coronavirion [J]. Proc Natl Acad Sci USA, 2009, 106(2):582-587.
[9] FEHR A R, PERLMAN S. Coronaviruses: an overview of their replication and pathogenesis [J]. Methods Mol Biol, 2015, 1282:1-23.
[10] LI F. Structure, Function, and Evolution of Coronavirus Spike Proteins [J]. Annu Rev Virol, 2016, 3(1):237-261.
[11] SCHOEMAN D, FIELDING B C. Coronavirus envelope protein: current knowledge [J]. Virol J, 2019, 16(1):69.
[12] CUI J, LI F, SHI Z L. Origin and evolution of pathogenic coronaviruses [J]. Nat Rev Microbiol, 2019, 17(3):181-192.
[13] WOO P C, LAU S K, LAM C S, et al. Discovery of seven novel Mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus [J]. J Virol, 2012, 86(7):3995-4008.
[14] LU R, ZHAO X, LI J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding [J]. The Lancet, 2020. https://doi.org/10.1016/S0140-6736(20)30251-8.
[15] ZHU N, ZHANG D, WANG W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019 [J]. New Engl J Med, 2020. https://doi.org/10.1056/NEJMoa2001017.
[16] BAEZ-SANTOS Y M, ST JOHN S E, MESECAR A D. The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds [J]. Antiviral Res, 2015, 115:21-38.
[17] CHAFEKAR A, FIELDING B C. MERS-CoV: Understanding the Latest Human Coronavirus Threat [J]. Viruses, 2018, 10(2):93.
[18] BOLLES M, DONALDSON E, BARIC R. SARS-CoV and emergent coronaviruses: viral determinants of interspecies transmission [J]. Curr Opin Virol, 2011, 1(6):624-634.
[19] LI W, MOORE M J, VASILIEVA N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus [J]. Nature, 2003, 426(6965):450-454.
[20] QIAN Z, TRAVANTY E A, OKO L, et al. Innate immune response of human alveolar type II cells infected with severe acute respiratory syndrome-coronavirus [J]. Am J Respir Cell Mol Biol, 2013, 48(6):742-748.
[21] RAJ V S, MOU H, SMITS S L, et al. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC [J]. Nature, 2013, 495(7440):251-254.
[22] LU G, WANG Q, GAO G F. Bat-to-human: spike features determining 'host jump' of coronaviruses SARS-CoV, MERS-CoV, and beyond [J]. Trends Microbiol, 2015, 23(8):468-478.
[23] CHAN J F, TO K K, TSE H, et al. Interspecies transmission and emergence of novel viruses: lessons from bats and birds [J]. Trends Microbiol, 2013, 21(10):544-555.
[24] GUAN Y, ZHENG B J, HE Y Q, et al. Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China [J]. Science, 2003, 302(5643):276-278.
[25] WU F, ZHAO S, YU B, et al. A new coronavirus associated with human respiratory disease in China [J]. Nature, 2020. https://doi.org/10.1038/s41586-020-2008-3.
[26] ZHOU P, YANG X-L, WANG X-G, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin [J]. Nature, 2020. https://doi.org/10.1038/s41586-020-2012-7.
[27] LI X, ZAI J, WANG X, et al. Potential of large 'first generation' human-to-human transmission of 2019-nCoV [J]. J Med Virol, 2020. https://doi.org/10.1002/jmv.25693.
[28] LU C W, LIU X F, JIA Z F. 2019-nCoV transmission through the ocular surface must not be ignored [J]. The Lancet, 2020. https://doi.org/10.1016/S0140-6736(20)30313-5.
[29] ZHANG H, KANG Z, GONG H, et al. The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes [J]. 2020. https://doi.org/10.1101/2020.01.30.927806.
[30] FAVRE G, POMAR L, MUSSO D, et al. 2019-nCoV epidemic: what about pregnancies? [J]. The Lancet, 2020. https://doi.org/10.1016/S0140-6736(20)30311-1.
[31] BACKER J A, KLINKENBERG D, WALLINGA J. Incubation period of 2019 novel coronavirus (2019-nCoV) infections among travellers from Wuhan, China, 20-28 January 2020 [J]. Eurosurveillance, 2020, 25(5). https://doi.org/10.1016/S0140-6736(20)30313-5.
[32] GUAN W J, NI Z Y, HU Y, et al. Clinical characteristics of 2019 novel coronavirus infection in China [J]. Med Rxiv, 2020. https://doi.org/10.1101/2020.01.30.927806.
[33] HUANG C, WANG Y, LI X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China [J]. The Lancet, 2020. https://doi.org/10.1016/S0140-6736(20)30311-1.
[34] MOMATTIN H, MOHAMMED K, ZUMLA A, et al. Therapeutic Options for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) - possible lessons from a systematic review of SARS-CoV therapy [J]. Int J Infect Dis, 2013, 17(10):e792-e798.
[35] OMRANI A S, SAAD M M, BAIG K, et al. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study [J]. The Lancet Infectious Diseases, 2014, 14(11):1090-1095.
[36] WIDAGDO W, OKBA N M A, STALIN RAJ V, et al. MERS-coronavirus: From discovery to intervention [J]. One Health, 2017, 3:11-16.
[37] ZUMLA A, CHAN J F, AZHAR E I, et al. Coronaviruses - drug discovery and therapeutic options [J]. Nat Rev Drug Discov, 2016, 15(5):327-347.
[38] RUSSELL C D, MILLAR J E, BAILLIE J K. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury [J]. The Lancet, 2020, 395(10223): 473-475.
[39] KNOWLES S R, PHILLIPS E J, DRESSER L, et al. Common adverse events associated with the use of ribavirin for severe acute respiratory syndrome in Canada [J]. Clin Infect Dis, 2003, 37(8):1139-1142.
[40] FALZARANO D, DE WIT E, RASMUSSEN A L, et al. Treatment with interferon-alpha2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques [J]. Nat Med, 2013, 19(10):1313-1317.
[41] CHENG V C, LAU S K, WOO P C, et al. Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection [J]. Clin Microbiol Rev, 2007, 20(4):660-694.
[42] PEIRIS J S M, CHU C M, CHENG V C C, et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study [J]. The Lancet, 2003, 361(9371):1767-1772.
[43] AGOSTINI M L, ANDRES E L, SIMS A C, et al. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease [J]. mBio, 2018, 9(2):doi: 10.1128/mBio.00221-18.
[44] JACOBS M, RODGER A, BELL D J, et al. Late Ebola virus relapse causing meningoencephalitis: a case report [J]. The Lancet, 2016, 388(10043):498-503.
[45] MULANGU S, DODD L E, DAVEY R T JR, et al. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics [J]. N Engl J Med, 2019, 381(24):2293-2303.
[46] DE WILDE A H, JOCHMANS D, POSTHUMA C C, et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture [J]. Antimicrob Agents Chemother, 2014, 58(8):4875-4884.
[47] SHEAHAN T P, SIMS A C, LEIST S R, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV [J]. Nat Commun, 2020, 11(1):DOI: 10.1038/s41467-019-13940-6
[48] HOLSHUE M L, DEBOLT C, LINDQUIST S, et al. First Case of 2019 Novel Coronavirus in the United States [J]. N Engl J Med, 2020. https://doi.org/10.1056/NEJMoa2001191.
[49] VAN DER LAAN L E, GARCIA-PRATS A J, SCHAAF H S, et al. Pharmacokinetics and Drug-Drug Interactions of Lopinavir-Ritonavir Administered with First- and Second-Line Antituberculosis Drugs in HIV-Infected Children Treated for Multidrug-Resistant Tuberculosis [J]. Antimicrob Agents Chemother, 2018, 62(2):DOI: 10.1128/AAC.00420-17.
[50] MEYNARD J L, MOINOT L, LANDMAN R, et al. Week 96 efficacy of lopinavir/ritonavir monotherapy in virologically suppressed patients with HIV: a randomized non-inferiority trial (ANRS 140 DREAM) [J]. J Antimicrob Chemother, 2018, 73(6):1672-1676.
[51] CHU C M, CHENG V C, HUNG I F, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings [J]. Thorax, 2004, 59(3):252-256.
[52] JI M. Darunavir Stands Up as Preferred HIV Protease Inhibitor. [J]. AIDS Rev, 2017,19(2):105-112.
[53] HOFFMANN M, KLEINE-WEBER H, KRüGER N, et al. The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells [J]. 2020. https://doi.org/10.1101/2020.01.31.929042.
[54] HAMMING I, TIMENS W, BULTHUIS M L, et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis [J]. J Pathol, 2004, 203(2):631-637.
[55] HEURICH A, HOFMANN-WINKLER H, GIERER S, et al. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein [J]. J Virol, 2014, 88(2):1293-1307.
[56] SHEN L W, MAO H J, WU Y L, et al. TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections [J]. Biochimie, 2017, 142:1-10.
[57] DELANG L, ABDELNABI R, NEYTS J. Favipiravir as a potential countermeasure against neglected and emerging RNA viruses [J]. Antiviral Res, 2018, 153:85-94.
[58] FURUTA Y, GOWEN B B, TAKAHASHI K, et al. Favipiravir (T-705), a novel viral RNA polymerase inhibitor [J]. Antiviral Res, 2013, 100(2):446-454.
[59] FURUTA Y, KOMENO T, NAKAMURA T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase [J]. Proc Japan Acad, Series B, 2017, 93(7):449-463.
[60] FINK S L, VOJTECH L, WAGONER J, et al. The Antiviral Drug Arbidol Inhibits Zika Virus [J]. Sci Rep, 2018, 8(1):doi: 10.1038/s41598-018-27224-4.
[61] PCHEUR E-I, BORISEVICH V, HALFMANN P, et al. The Synthetic Antiviral Drug Arbidol Inhibits Globally Prevalent Pathogenic Viruses [J]. J Virology, 2016, 90(6):3086-3092.
[62] NAKAMURA M, SAITO H, IKEDA M, et al. An antioxidant resveratrol significantly enhanced replication of hepatitis C virus [J]. World J Gastroenterol, 2010, 16(2):184-192.
[63] DRAGO L, NICOLA L, OSSOLA F, et al. In vitro antiviral activity of resveratrol against respiratory viruses [J]. J Chemother, 2008, 20(3):393-394.
[64] CAMPAGNA M, RIVAS C. Antiviral activity of resveratrol [J]. Biochem Soc Trans, 2010, 38(Pt 1):50-53.
[65] LIN S C, HO C T, CHUO W H, et al. Effective inhibition of MERS-CoV infection by resveratrol [J]. BMC Infect Dis, 2017, 17(1): doi: 10.1186/s12879-017-2253-8.
[66] ABBA Y, HASSIM H, HAMZAH H, et al. Antiviral Activity of Resveratrol against Human and Animal Viruses [J]. Adv Virol, 2015, 2015. doi: 10.1155/2015/184241.
[67] MCBRIDE R, VAN ZYL M, FIELDING B C. The coronavirus nucleocapsid is a multifunctional protein [J]. Viruses, 2014, 6(8):2991-3018.
[68] SAMUEL C E. Antiviral actions of interferons [J]. Clin Microbiol Rev, 2001, 14(4):778-809.
[69] MENACHERY V D, EISFELD A J, SCHAFER A, et al. Pathogenic influenza viruses and coronaviruses utilize similar and contrasting approaches to control interferon-stimulated gene responses [J]. mBio, 2014, 5(3):1-11.
[70] SIU K L, YEUNG M L, KOK K H, et al. Middle east respiratory syndrome coronavirus 4a protein is a double-stranded RNA-binding protein that suppresses PACT-induced activation of RIG-I and MDA5 in the innate antiviral response [J]. J Virol, 2014, 88(9):4866-4876.
[71] ROSSIGNOL J F. Nitazoxanide: a first-in-class broad-spectrum antiviral agent [J]. Antiviral Res, 2014, 110:94-103.
[72] HAFFIZULLA J, HARTMAN A, HOPPERS M, et al. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial [J]. The Lancet Infect Dis, 2014, 14(7):609-618.
[73] DE WILDE A H, PHAM U, POSTHUMA C C, et al. Cyclophilins and cyclophilin inhibitors in nidovirus replication [J]. Virology, 2018, 522:46-55.
[74] OLEJNIK P, NUC K. [Cyclophilins- proteins with many functions] [J]. Postepy Biochem, 2018, 64(1):46-54.
[75] WANG P, HEITMAN J. The cyclophilins [J]. Genome Biol, 2005, 6(7):226.
[76] PFEFFERLE S, SCHOPF J, KOGL M, et al. The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors [J]. PLoS Pathog, 2011, 7(10):e1002331.
[77] TANAKA Y, SATO Y, SASAKI T. Suppression of coronavirus replication by cyclophilin inhibitors [J]. Viruses, 2013, 5(5):1250-1260.
[78] DE WILDE A H, ZEVENHOVEN-DOBBE J C, VAN DER MEER Y, et al. Cyclosporin A inhibits the replication of diverse coronaviruses [J]. J Gen Virol, 2011, 92(Pt 11):2542-2548.
[79] TANAKA Y, SATO Y, OSAWA S, et al. Suppression of feline coronavirus replication in vitro by cyclosporin A [J]. Vet Res, 2012, 43(1):41.
[80] SAVARINO A, DI TRANI L, DONATELLI I, et al. New insights into the antiviral effects of chloroquine [J]. Lancet Infect Dis, 2006, 6(2):67-69.
[81] WANG M, CAO R, ZHANG L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro [J]. Cell Res, 2020. https://doi.org/10.1038/s41422-020-0282-0.
[82] INOUE Y, TANAKA N, TANAKA Y, et al. Clathrin-dependent entry of severe acute respiratory syndrome coronavirus into target cells expressing ACE2 with the cytoplasmic tail deleted [J]. J Virol, 2007, 81(16):8722-8729.
[83] SISK J M, FRIEMAN M B, MACHAMER C E. Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors [J]. J Gen Virol, 2018, 99(5):619-630.
[84] COLEMAN C M, SISK J M, MINGO R M, et al. Abelson Kinase Inhibitors Are Potent Inhibitors of Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus Fusion [J]. J Virol, 2016, 90(19):8924-8933.
[85] JIN Y, LEI C, HU D, et al. Human monoclonal antibodies as candidate therapeutics against emerging viruses [J]. Front Med, 2017, 11(4):462-470.
[86] HAN H J, LIU J W, YU H, et al. Neutralizing Monoclonal Antibodies as Promising Therapeutics against Middle East Respiratory Syndrome Coronavirus Infection [J]. Viruses, 2018, 10(12):680.
[87] XU J, JIA W, WANG P, et al. Antibodies and vaccines against Middle East respiratory syndrome coronavirus [J]. Emerg Microbes Infect, 2019, 8(1):841-856.
[88] PASCAL K E, COLEMAN C M, MUJICA A O, et al. Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection [J]. Proc Natl Acad Sci USA, 2015, 112(28):8738-8743.
[89] CASADEVALL A, PIROFSKI L A. The Ebola epidemic crystallizes the potential of passive antibody therapy for infectious diseases [J]. PLoS Pathog, 2015, 11(4):e1004717.
[90] KECK Z Y, WANG Y, LAU P, et al. Isolation of HCV Neutralizing Antibodies by Yeast Display [J]. Methods Mol Biol, 2019, 1911:395-419.
[91] SHIN Y W, CHANG K H, HONG G W, et al. Selection of Vaccinia Virus-Neutralizing Antibody from a Phage-Display Human-Antibody Library [J]. J Microbiol Biotechnol, 2019, 29(4):651-657.
[92] MIRE C E, GEISBERT J B, AGANS K N, et al. Passive Immunotherapy: Assessment of Convalescent Serum Against Ebola Virus Makona Infection in Nonhuman Primates [J]. J Infect Dis, 2016, 214(suppl 3):S367-S74.
[93] MARANO G, VAGLIO S, PUPELLA S, et al. Convalescent plasma: new evidence for an old therapeutic tool? [J]. Blood Transfus, 2016, 14(2):152-157.
[94] 段相宇. 解读新冠病毒特免血浆制品是什么? [EB/OL]. http://www.hbsjcj.gov.cn/sitesources/hbsjcj/page_pc/jjrd/article52f03166e9764b1ca86a649402b3b297.html, 2020-02-14.

基金

中国医学科学院医学与健康科技创新工程基金资助项目(2017-I2M-1-011)
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