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司龙龙: 学科交叉促进科研创新

2018年是贯彻落实党的十九大精神的开局之年,也是北大建校120周年和全面推进“双一流”建设的关键一年。研究生院以建设世界一流水平的研究生教育体系为目标,以“北京大学博士研究生教育综合改革”为抓手,在研究生培养管理、资助体系、学科交叉、国际化等方面采取了一系列举措,旨在推动研究生培养质量的全面提高,实现北大研究生教育的内涵式发展。藉此契机,研究生院将推出“青春的榜样——北京大学优秀博士生”系列访谈报道,希望以这些优秀的博士生为榜样,激励更多的研究生同学刻苦学习、不懈努力,成为“有理想、有本领、有担当”的拔尖创新人才。

司龙龙,北京大学药学院天然药物及仿生药物国家重点实验室化学生物学专业2012级直博生,导师周德敏教授。主要从事抗病毒药物开发、作用机制研究;及基于基因密码子扩展技术的复制可控的活病毒疫苗技术开发。攻读博士期间,在国际著名期刊Science、J. med.chem.、Biomaterials等发表论文25篇,参与申请专利9项;曾获得“中国大学生年度人物”、“北京大学学生年度人物”、北京大学“学术十杰”、“北京市优秀毕业生”、“北京大学优秀毕业生”、北京大学医学部“学术之星·冠军”、“博士研究生国家奖学金”、北京大学“创新奖”、北京大学“学习优秀奖”、北京大学“优秀科研奖”、第一届国际青年生命科学家亦庄论坛“优秀墙报奖”、北京大学“春雨奖学金”、北京大学“扬子江药业奖学金”、北京大学“卓越83奖学金”等荣誉和奖励。2017年博士毕业后,赴美国哈佛大学开展生物医学工程方向的博士后研究。

    “2012-2017年,在北京大学药学院天然药物及仿生药物国家重点实验室度过的5年博士生涯,已成为我人生中一段宝贵的成长经历。虽然毕业已近一年,但是昔日在困难面前的彷徨、在失败后的忧伤、以及取得突破获得成功后的激动昂扬,依然历历在目。感恩导师、学院、学校给予我们的培养与教育、以及为我们提供优越的学术平台和氛围。以下是我的一点个人感悟,希望对母校的师弟师妹们有所帮助。”

学科交叉促科研创新

我在科研中取得的成果,很大程度上得益于化学-生物学科高度交叉融合。在进入博士学习阶段之前,我主要学习的是化学相关的知识和实验;而博士期间,我的专业是化学生物学。最初,我并不懂得化学生物学的真正内涵,只是知道我们一群既做化学又做生物的人;科研闲暇之余我还常常在担心,毕竟人的时间和精力是有限的,我们从事化学生物学研究的结局,会不会导致我们做化学做得不如化学学院的学生,做生物做得不如生命科学学院的学生?而随着学习的深入,逐渐了解到化学生物学是一门新型的学科,旨在利用化学作为工具,探索、解析、调控复杂的生物体系。

 

我在进行抗病毒药物作用靶点的研究中,第一次真正体会化学-生物交叉学科的优势:在病毒与细胞相互作用的复杂体系中存在成千上万个蛋白,用传统的生物学方法从中快速精准地找到药物的作用靶点,是相当困难的,甚至是不可能的;而通过发挥化学-生物学交叉学科的优势,我们可以在药物分子上修饰具有“光交联”功能的化学基团,从而将药物设计成化学探针,它可以在特定波长紫外光的照射下,“捕获”与药物分子相互作用的靶蛋白,结合蛋白质质谱技术就可以鉴定药物分子的靶蛋白和结合位点,从而推动药物作用机制研究和新药开发。

 

而我在进行复制可控的病毒活疫苗研究中,深刻地体会到了化学-生物学科交叉可以为我们提供无限的科研想象和发挥空间。在该研究中,我们将小分子化合物作为病毒复制的开关,使得病毒只在我们的病毒生产体系中进行大规模复制,而在人体中失去复制能力,从而将病毒转化成了安全的疫苗。对我个人而言,该项研究的意义不仅仅在于发表了一篇Science论文,更重要的是它证实了利用化学手段调控和改造生命体的可能性,展现了学科交叉融合对于科研创新的无穷魅力。学科交叉不仅仅是化学、生物学学科的交叉,也不仅仅是知识和技术层面的交流,更重要的是它告知我们学会从不同角度、使用不同思维方式发现和解决科学问题的重要性。显然,北大的“思想自由、兼容并包”的优良传统,为学科交叉融合提供了优良的条件,进而为科研创新提供了沃土。

自由开放的学习科研氛围

 

北大的自由、开放,不仅体现在学科交叉上,还体现在日常的学习、工作、生活之中。作为北大的一个缩影,在我们实验室,我们导师常常将培养学生比喻成“钓鱼”——“授之以鱼,不如授之以渔”;他不会强制学生做某个课题,而通常是提议一个大的研究方向,给予学生很大的自由发挥空间;所以实验室的学生完全可以根据自己的兴趣,选择做化学还是做生物,或者两者都做;而不管学生有任何科研上的想法与导师讨论,听到的我们导师最常说的一句话就是“好,没问题,去做就行了”。 

 

我想类似的实验室在北大一定有很多,在这里,你可以大胆地向导师表达自己的科学观点,不必畏手畏脚;在这里,你可以参加各种各样的学术沙龙和讲座,与老师、同学交流,碰撞火花;在这里,所有的努力都会得到尊重。当手脚没有受到限制,思维与灵感就不会受到禁锢。与考试分数和发表论文数量相比,北大给予我们每一个学生思维的培养更为重要,因为它可以让我们终生受益。

身在异国,心系母校。值此北大120年华诞,再次感恩母校这个成就了无数学子梦想的舞台;祝愿母校年年桃李,岁岁芬芳!

致谢博士期间的研究团队

从右往左:张礼和院士、周德敏教授、司龙龙

 

文章发表

 

1. Longlong Si, Huan Xu, Xueying Zhou, Ziwei Zhang, Zhenyu Tian, Yiming Wu, Bo Zhang, Yan Wang, Zhenglan Niu, Chuanling Zhang, Ge Fu, Sulong Xiao, Qing Xia, Lihe Zhang, Demin Zhou. Generation of influenza A viruses as live but replication-incompetent virus vaccines. Science, 2016, 354, 1170-1173.

2. Sulong Xiao, Longlong Si (co-first author), Zhenyu Tian, Pingxuan Jiao, Zibo Fan, Kun Meng, Xiaoshu Zhou, Han Wang, Renyang Xu, Xu Han, Ge Fu, Yongmin Zhang,Lihe Zhang, Demin Zhou. Pentacyclic triterpenes grafted on CD cores to interfere with influenza virus entry: A dramatic multivalent effect. Biomaterials 2016, 78, 74-85.

3.Maorong Yu, Longlong Si (co-first author), Yufei Wang, Yiming Wu,Fei Yu, Pingxuan Jiao, Yongying Shi, Han Wang, Sulong Xiao, Ge Fu, Ke Tian,Yitao Wang, Zhihong Guo, Xinshan Ye, Lihe Zhang, Demin Zhou. Discovery of pentacyclic triterpenoids as potential entry inhibitors of influenza viruses. J. Med. Chem. 2014, 57, 10058-10071.

4. Xueqing Chen, Longlong Si (co-first author), Dong Liu, Peter Proksch, Lihe Zhang, Demin Zhou, Wenhan Lin. Neoechinulin B and its analogues as potential entry inhibitors of influenza viruses, targeting viral hemagglutinin. Eur. J. Med. Chem. 2015, 93, 182-195.

5.Siwen Niu, Longlong Si (co-first author), Dong Liu, Andrew Zhou, Ziwei Zhang, Zongze Shao, Shaomeng Wang, Lihe Zhang, Demin Zhou, Wenhan Lin. Spiromastilactones: A new class of influenza virus inhibitors from deep-sea fungus. Eur. J. Med. Chem. 2015, 108, 229-244.

6. Zhenyu Tian, Longlong Si (co-first author), Kun Meng, Xiaoshu Zhou, Yongmin Zhang, Demin Zhou, Sulong Xiao. Inhibition of influenza virus infection by multivalent pentacyclic triterpene-functionalized per-O-methylated cyclodexrin conjugates. Eur. J. Med. Chem. 2017, DOI: 10.1016/j.ejmech.2017.03.087.

7. Yongying Shi, Longlong Si (co-first author), Xu Han, Zibo Fan, Shouxin Wang, Man Li, Jiaqi Sun, Yongmin Zhang, Demin Zhou, Sulong Xiao. Synthesis of novel pentacyclic triterpene-Neu5Ac2en derivatives and investigation of their in vitro anti-influenza entry activity. Med. Chem. Comm. 2017, DOI: 10.1039/C7MD00245A.

8. Xu Han, Longlong Si (co-first author), Yongying Shi, Zibo Fan, Shouxin Wang, Zhenyu Tian, Man Li, Jiaqi Sun, Pingxuan Jiao, Fuxiang Ran, Yongmin Zhang, Demin Zhou, Sulong Xiao. Synthesis and in vitro anti-influenza virus evaluation of novel sialic acid (C-5 and C-9)-pentacyclic triterpene derivatives. Molecules, 2017, 22,1018.

9. Wu, L.; Chen, J.; Wu, Y.; Zhang, B.; Cai, X.; Zhang, Z.; Wang, Y.; Si, L.; Xu, H.; Zheng, Y.; Zhang, C.; Liang, C.; Li, J.; Zhang, L.; Zhang, Q.; Zhou, D. Precise and combinatorial PEGylation generates a low-immunogenic and stable form of human growth hormone. J Control Release 2017, 249, 84-93.

10. Yiming Wu, Hua Zhu, Bo Zhang, Longlong Si, Huan Xu, Sulong Xiao, Lihe Zhang, Demin Zhou. Synthesis of Site-Specific Radiolabeled Antibodies for Radioimmunotherapy via Genetic Code Expansion. Bioconjugate Chem. 2016, 27, 2460-2468.

11. Wu, S.; Yang, L.; Sun, W.; Si, L.; Xiao, S.; Wang, Q.; Dechoux, L.; Thorimbert, S.; Sollogoub, M.; Zhou, D.; Zhang, Y. Design, synthesis and biological evaluation of gentiopicroside derivatives as potential antiviral inhibitors. Eur J Med Chem. 2017, 130, 308-319.

12. Wei Song, Longlong Si, Shuai Ji, Han Wang, Xiaomei Fang, Li-yan Yu, Renyong Li, Li-na Liang, Demin Zhou, Min Ye. Uralsaponins M-Y, antiviral triterpenoid saponins from the roots of Glycyrrhiza uralensis. J. Nat. Prod. 2014, 77, 1632-1643.

13. Aigang Yang, Longlong Si, Zhenping Shi, Li Tian, Dong Liu, Demin Zhou, Peter Proksch, Wenhan Lin. Nitrosporeusines A and B, Unprecedented Thioester-Bearing Alkaloids from the Arctic Streptomyces nitrosporeus. Organic Letters, 2013, 15, 5366-5369.

14. Yang Zhao, Longlong Si, Dong Liu, Peter Proksch, Demin Zhou, Wenhan Lin. Truncateols AeN, new isoprenylated cyclohexanols from the sponge-associated fungus Truncatella angustata with anti-H1N1 virus activities. Tetrahedron 2015, 71, 2708-2718.

15. Sulong Xiao, Qi Wang, Longlong Si, Yongying Shi, Han Wang, Fei Yu, Yongmin Zhang, Yingbo Li, Yongxiang Zheng, Chuanling Zhang, Chunguang Wang, Lihe Zhang, Demin Zhou. Synthesis and anti-HCV entry activity studies of beta-cyclodextrin-pentacyclic triterpene conjugates. ChemMedChem 2014, 9, 1060-1070.

16. Sulong Xiao, Qi Wang, Longlong Si, Xiaoshu Zhou, Yongmin Zhang, Lihe Zhang, Demin Zhou. Synthesis and biological evaluation of novel pentacyclic triterpene a-cyclodextrin conjugates as HCV entry inhibitors. Eur J Med Chem, 2016, 124, 1-9.

17. Xu Han, Yongying Shi, Longlong Si, Zibo Fan, Han Wang, Renyang Xu, Pingxuan Jiao, Kun Meng, Zhenyu Tian, Xiaoshu Zhou, Hongwei Jin, Yongmin Zhang, Lihe Zhang, Sulong Xiao, Demin Zhou. Design, synthesis and biological activity evaluation of novel conjugated sialic acid and pentacyclic triterpene derivatives as anti-influenza entry inhibitors. MedChemComm, 2016, DOI: 10.1039/C6MD00292G.

18. Yongxiang Zheng, Fei Yu, Yiming Wu, Longlong Si, Huan Xu, Chuanling Zhang, Qing Xia, Sulong Xiao, Qi Wang, Qiuchen He, Peng Chen, Jiangyun Wang, Kazunari Taira, Lihe Zhang, Demin Zhou. Broadening the versatility of lentiviral vectors as a tool in nucleic acid research via genetic code expansion. Nucleic Acids Res 2015, 43, e73.

19. Han Wang, Renyang Xu, Yongying Shi, Longlong Si, Pingxuan Jiao, Zibo Fan, Xu Han, Xingyu Wu, Xiaoshu Zhou, Fei Yu, Yongmin Zhang, Liangren Zhang, Lihe Zhang, Demin Zhou, Sulong Xiao. Design, synthesis and biological evaluation of novel l-ascorbic acid-conjugated pentacyclic triterpene derivatives as potential influenza virus entry inhibitors. Eur J Med Chem 2016, 110, 376-388.

20. Fei Yu, Yiyun Peng, Qi Wang, Yongying Shi, Longlong Si, Han Wang, Yongxiang Zheng, Emily Lee, Sulong Xiao, Yingbo Li, Hengli Tang, Chunguang Wang, Lihe Zhang, Demin Zhou. Development of bivalent oleanane-type triterpenes as potent HCV entry inhibitors. Eur J Med Chem 2014, 77, 258-268.

21. Shuai Ji, Ru Li, Qi Wang, Wenjuan Miao, Ziwei Li, Longlong Si, Xue Qiao, Siwang Yu, Demin Zhou, Min Ye. Anti-H1N1 virus, cytotoxic and Nrf2 activation activities of chemical constituents from Scutellaria baicalensis. J Ethnopharmacol 2015, 176, 475-484.

22. Fei Yu, Qi Wang, Han Wang, LongLong Si, JiaXin Liu, Xu Han, Su-Long Xiao, Li-He Zhang, Demin Zhou. Synthesis and biological evaluation of echinocystic acid derivatives as HCV entry inhibitors. Chinese Chemical Letters 2016, 27, 711–713.  

23. Bo Zhang, Huan Xu, Jingxian Chen, Yongxiang Zheng, Yiming Wu, Longlong Si, Ling Wu, Chuanling Zhang, Gang Xia, Lihe Zhang, Demin Zhou. Development of next generation of therapeutic IFN-a2b via genetic code Expansion. Acta Biomaterialia 2015, 19, 100–111.

24. Huan Xu, Yan Wang, Jiaqi Lu, Bo Zhang, Ziwei Zhang, Longlong Si, Ling Wu, Tianzhuo Yao, Chuanling Zhang, Sulong Xiao, Lihe Zhang, Qing Xia, Demin Zhou. Re-exploration of the Codon Context Effect on Amber Codon-Guided Incorporation of Noncanonical Amino Acids in Escherichia coli by the Blue-White Screening Assay. Chembiochem 2016, 17, 1250-1256.

25. Sulong Xiao, Zhenyu Tian, Yufei Wang, Longlong Si, Lihe Zhang, Demin Zhou. Recent progress in the antiviral activity and mechanism study of pentacyclic triterpenoids and their derivatives. Med. Res. Rev. 2018, Med Res Rev, doi:10.1002/med.21484.

专利申请

1. PCT/CN2016/092778 Demin Zhou, Longlong Si, Lihe Zhang, et al. Mutant viruses, their preparation methods and applications.

2. 201511029463.1 Demin Zhou, Longlong Si, Lihe Zhang, et al. Site-directed mutant influenza viruses, live vaccines, and their preparation methods and applications.

3. 201610248269.0 Demin Zhou, Longlong Si, Lihe Zhang, et al. Triterpenoid derivatives and their applications as anti-Ebola virus inhibitors.

4. 201410541586.2 Wenhan Lin, Demin Zhou, Longlong Si, et al. A new class of polyketides, their preparation methods and applications as anti-influenza virus inhibitors.

5. 201410289156.6 Xueqing Chen, Longlong Si, Wenhan Lin, Demin Zhou, et al. The applications of Neoechinulin B as anti-influenza virus inhibitors

6. 201310684679.6 Demin Zhou, Sulong Xiao, Yongying Shi, Longlong Si, Lihe Zhang, et al. A new class of covalent triterpenoid-cyclodextrin conjugates, their preparation methods and applications.

7. 201610055542.8 Demin Zhou, Huan Xu, Bo Zhang, Longlong Si, Lihe Zhang, et al. The establishment of a stable cell line carrying orthogonal tRNA/Aminoacyl tRNA synthetase.

8. 201310524527.X Demin Zhou, Chuanling Zhang, Sulong Xiao, Yongxiang Zheng, Fei Yu, Longlong Si, Lihe Zhang. Site-directed and site-modified adeno-associated virus, their preparation methods and applications.

9.201310654389.3 Demin Zhou, Ling Wu, Bo Zhang, Jingxian Chen, Longlong Si, Lihe Zhang. Site-modified recombinant interferon-α2β with polyethylene glycol.

 

 

 

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