科学研究 | 刘刚 博士

刘刚博士

教授、博士生导师

刘刚教授1994年毕业于北京医科大学药学院并获博士学位。1994年至1997年间前后于军事医学科学院毒物药物研究所及The Scripps Research Institute从事博士后研究工作。后作为高级研究助理在美国加州大学戴维斯分校工作三年。2000年回到中国医学科学院药物研究所建立了自己的实验室,并于同年及2005年被分别授予“协和学者”特聘教授及教育部“长江学者”特聘教授。2011年始任清华大学百人教授,在清华大学医学院负责筹建药学系,并担任首任药学系主任。曾兼任中华人民共和国农业部第五届兽药评审专家,现任Associate Editor of “Molecular Diversity”, Journal of Medicinal Chemistry、《中国药物化学杂志》、《中国药学》(英文版)、《药学学报》、《中国病毒病杂志》等期刊编委。曾主持美国国家健康研究所(NIH)R01抗SARS-CoV项目,参与Bill & Melinda Gates Foundation的抗结核项目;主持或参与过国家科技部(“863”,“973”)项目、国家重大新药创制项目、国家自然科学基金各类项目,人事部、教育部、卫生部以及企业等多项基金项目。出版《新药研究中的组合化学》一部、英文图书两章、中文图书一章。发表60余篇研究性论文。多次受邀在国际学术会议上进行大会口头报告。申请国际国内专利二十余项。一个抗肿瘤药物候选物(康莫他赛)向SFDA申报临床研究,目前在技术审评阶段。


研究方向

实验室主要研究小分子化合物化学库、天然产物、多肽/糖肽、以及“协同治疗”分子的合成方法;同时,实验室也研究高通量筛选方法用于了解分子间的相互作用、编码及解码可干扰生物活性作用的小分子化合物。实验室的目标是发现药物先导化合物并优化为药物候选物用于治疗癌症及感染性疾病。

科学贡献

刘刚教授是我国最早从事组合化学和化学生物学研究者之一,成功搭建了由高通量合成技术、高通量现代分析技术、药物化学、有机化学、高分子化学(树脂)、计算化学、自动化技术、生物筛选技术、数据管理系统、以及样品保存和质控分析方法等多学科和技术支撑的系统组合化学技术平台,被专家鉴定为“整体处于国际先进水平”。多年来在小分子杂环化合物化学库的设计与组合合成、多肽化学以及多肽模拟物化学、有机化学、药物化学、以及免疫治疗、抗肿瘤和抗感染性疾病的药物研究方面都积累了丰富的研究经验,取得了一些重要研究结果。
实验室发现的紫杉醇与胞壁酰二肽模拟物的共缀物“康莫他赛”,设计为协同抑制肿瘤微环境内的炎性细胞因子,进而抑制肿瘤的转移性生长,目前已申报SFDA并进入实审阶段等待批准临床研究。

主要研究成果

1.SARS冠状病毒抗原表位的研究:对非人类灵长类动物感染的增强或中和作用(ACS Infect. Dis. 2016, 2, 361−376.)。
 

Significance: Severe acute respiratory syndrome (SARS) is caused by a coronavirus (SARS-CoV) and has the potential to threaten global public health and socioeconomic stability. Evidence of antibody-dependent enhancement (ADE) of SARS-CoV infection in vitro and in non-human primates clouds the prospects for a safe vaccine. Using antibodies from SARS patients, we identified and characterized SARS-CoV B-cell peptide epitopes with disparate functions. In rhesus macaques, the spike glycoprotein peptides S471–503, S604–625 and S1164–1191 elicited antibodies that efficiently prevented infection in non-human primates. In contrast, peptide S597–603 induced antibodies that enhanced infection both in vitro and in non-human primates by using an epitope sequence-dependent (ESD) mechanism. This peptide exhibited a high level of serological reactivity (64%), which resulted from the additive responses of two tandem epitopes (S597–603 and S604–625), and a long-term human B-cell memory response with antisera from convalescent SARS patients. Thus, peptide-based vaccines against SARS-CoV could be engineered to avoid ADE via elimination of the S597-603 epitope. We provide herein an alternative strategy to prepare a safe and effective vaccine for ADE of viral infection by identifying and eliminating epitope sequence-dependent enhancement of viral infection.

2.Calanolide类似物的抗非复制性结核杆菌的研究J. Med. Chem., 2014, 57, 3755)。
 
  







Significance: Naturally occurring (+)-calanolide A was active against R Mtb. The present report details the design, synthesis, anti-mycobacterial activities and structure–activity relationships of synthetic calanolides. This study identified potent dual-active nitro-containing calanolides with minimal in vitro toxicity that was cidal to axenic Mtb (both replicating and non-replicating Mtb) and Mtb in human macrophages, while sparing Gram-positive and -negative bacteria and yeast.
3.抑制肿瘤生长及转移的MDP类似物MTC-220的研究J Med Chem 2011, 54(8): 2767-77; Glycoconj J 2008, 25: 415–425.)。

 
Significance: MTC-220, a conjugate of paclitaxel and a muramyl dipeptide analog has been synthesized as a novel agent of dual antitumor growth and metastasis activities. In vitro and in vivo tests show that MTC-220 retains its ability to inhibit tumor growth. It is superior to paclitaxel in its ability to prevent tumor metastasis in Lewis lung carcinoma and 4T1 tumor-bearing mice. The present studies indicate that MTC-220 suppresses myeloid derived suppressor cell accumulation in the spleen and bone marrow of tumor-bearing mice, and also represses inflammatory cytokines in tumor tissue. These results demonstrated that MTC-220 could be a potential therapeutic and preventive agent for cancer growth and metastasis.

4.交叉欧联类型的串联氯钯化/去芳香化/环化反应构建功能化的[3.2.1]桥环骨架类化合物。 (Org Lett 2015, 17(16): 4110-3.)。
Significance: A palladium-catalyzed tandem reaction is reported in this study that involves chloropalladation /cyclization and dearomative cyclization to construct tricyclic bridged [3.2.1] carbocyclic- skeleton and oxa- and aza-skeletons. In this domino process, a level of ring strain and other competitive reactions, i.e., protonolysis, b-hydride elimination, and chlorination of the C–Pd bond, were suppressed to the lowest level under mild reaction conditions.

5.新型抗HIV候选物小分子逆转录酶抑制剂F18的研究。Antimicrob Agents Chemother. 2012, 56(1): 341-51.)。
Significance: We have previously described a newly synthesized small molecule 10-chloromethyl-11-demethyl-12-oxo-calanolide A (F18), a nature (+)-Calanolide A analog, as a novel NNRTI to treat HIV-1 patients (J Med Chem. 2008, 51, 1432-1446; 2010, 53, 1397-1401).  This study presents F18 as a new potential drug for clinical use and also underlies new mechanism-based design for future NNRTI.

荣誉和奖项

1.教育部“长江学者”特聘教授,2005年
2.清华大学“百人计划”特聘教授,2011年
3.中国医学科学院,北京协和医院“协和学者”特聘教授,2000年
4.药明康德生命化学研究奖三等奖,2007年
5.北京市科学技术进步三等奖,2006年
6.中国分析测试协会科学技术奖(CAIA奖)三等奖,2005年

主要论文发表
 

1.Qidi Wang, Lianfeng Zhang, Kazuhiko Kuwahara, Li Li, Zijie Liu, Taisheng Li, Hua Zhu, Jiangning Liu, Yanfeng Xu, Jing Xie, Hiroshi Morioka, Nobuo Sakaguchi*, Chuan Qin*, Gang LIU*,Immunodominant SARS Coronavirus Epitopes in Humans Elicited both Enhancing and Neutralizing Effects on Infection in Non-Human Primates, ACS Infect. Dis. 2016, 2, 361−376. DOI: 10.1021/acsinfecdis.6b00006.
2.Chong Tian, Xiaoqiang Lei, Yuanhao Wang, Zhen Dong, Gang Liu* and Yefeng Tang*, Collective and Biomimetic Total Syntheses of Periconiasins A-E, Angew. Chem. Int. Ed., 2016, DOI:10.1002/anie.201602439
3.Nan Zhao, Mingna Sun, Kristin E. Burns-Huang, Xiuju Jiang, Yan Ling, Crystal M. Darby, Sabine Erht, Gang Liu* and Carl F. Nathan*, Identification of Rv3852 as an Agrimophol-Binding Protein in Mycobacterium tuberculosis, PLoS One. 2015, 10(5): e0126211. doi: 10.1371/journal.pone.0126211.
4.Xueyuan Li, Yi Dong, Fengyu QU*, Gang Liu*. Synthesis of benzofused five-ring sultams via Rh-catalyzed CH olefination directed by an N-Ac substituted sulfonamide group, J Org Chem 2015, 80, 790−798.
5.Yi Dong, Nana Du, Xueyuan Li, Litao Zheng, Gang Liu*, Cross-coupling type tandem chloropalladation/dearomative cyclization towards functionalized bridged [3.2.1] skeleton compounds, Org Lett 2015, 17(16):4110-3.
6.Purong Zheng, Selin Somersan Karakaya, Shichao Lu, Julia Roberts, Maneesh Pingle, Thulasi Warrier, David Little, Xiaoyong Guo, Steven Brickner, Carl F. Nathan*, Ben Gold*, Gang Liu* Synthetic Calanolides with Bactericidal Activity Against Replicating and Non-replicating Mycobacterium tuberculosiss, J Med Chem 2014, 57(9), 3755–3772.
7.Hong-Shuang Li, Gang Liu *, Copper/Silver-Mediated Cascade Reactions for the Construction of 2-Sulfonylbenzo[b]furans from trans-2-Hydroxycinnamic Acids and Sodium Sulfinates, J Org Chem 2014, 79, 509−516.
8.Bo Liu, Fa Zhang, Yan Zhang, Gang Liu*, A new approach for the synthesis of O-glycopeptides through a combination of solid-phase glycosylation and fluorous tagging (SHGPFT), Org. Biomol. Chem., 2014, 12, 1892–1896.
9.Xilei Xie, Yu Yan, Ning Zhu, Gang Liu*, Benzothiazoles exhibit broad-spectrum antitumor activity: their potency, structure-activity and structure-metabolism relationships, Eur J Med Chem 2014, 76, 67-78.
10.Yaling Gong, Selin Somersan Karakaya, Purong Zheng, Ben Gold, David Little, Julia Roberts, Thulasi Warrier, Xiuju Jiang, Maneesh Pingle, Carl F. Nathan*, Gang Liu*, Benzimidazole-Based Compounds Kill Mycobacterium tuberculosis, Eur J Med Chem 2014, 75, 336-353.
11.Yingwei Hou, Shichao Lu and Gang Liu*, Iodine (III)-mediated [3+2] cyclization for one-pot synthesis of benzo[d]isoxazole-4,7-diol, benzodiisoxazole-4,8-diol, isoxazole[5,4-a]phenazine and indazole-4,7-diol in aqueous medium, J Org Chem 2013, 78, 8386−8395.
12.Yi Dong, Gang Liu*,Rh-Catalyzed Sulfonic Acid Group Directed C-H Olefination of Arenes, Chem Comm, 2013, 49, 8066-8068.
13.Mingna Sun, Jinfeng Hu, Xiuyun Song, Donghui Wu, Linglei Kong, Yupeng Sun, Dongmei Wang, Yan Wang*, Naihong Chen* and Gang Liu*, Coumarin Derivatives Protect Against Ischemic Brain Injury in Rats, Eur J Med Chem 2013, 67, 39-53.
14.Crystal M. Darby, Helgi I. Ingólfsson, Xiuju Jiang, Chun Shen, Mingna Sun, Nan Zhao, Kristin Burns, Gang Liu, Sabine Ehrt, J. David Warren, Olaf S. Anderson, Steven J. Brickner, and Carl Nathan*, Whole cell screen for inhibitors of pH homeostasis in Mycobacterium tuberculosis, PLOS ONE, 2013, 8(7), e68942.
15.Shichao Lu, Purong Zheng, Gang Liu*, Iodine(III)-Mediated Tandem Oxidative Cyclization for Construction of 2-Nitrobenzo[b]furans, J Org Chem 2012, 77, 7711-7717.
16.Xiaofan Lu, Li Liu, Xu Zhang, Terrence Lau, Stephen Kwok-Wing Tsui,   Yuanxi Kang,  Purong Zheng, Gang Liu* and Zhiwei Chen*, F18, a novel small molecule NNRTI, inhibits HIV-1 replication using distinct binding motifs, Antimicrob Agents Chemother. 2012, 56(1): 341-351.
17.Rui Liu, Zhuhui Huang, Michael G. Murray, Xiaoyong Guo, Gang Liu*, Quinoxalin-2(1H)-One Derivatives As Inhibitors Against Hepatitis C Virus, J Med  Chem 2011, 54, 5747–5768.
18.Yao Ma, Nan Zhao, Gang Liu*, Muramyl Dipeptide’s Derivative and Paclitaxel Conjugate (MTC-220) Simultaneously Prevents Tumor Growth and Metastasis in Mice, J  Med  Chem 2011, 54(8): 2767-77.
19.Gang Li, Dongmei Wang, Mingna Sun, Guangyan Li, Jinfeng Hu, Yun Zhang, Yuhe Yuan, Haijie Ji, Naihong Chen*, Gang Liu[i]*. Discovery and Optimization of Novel 3-Piperazinyl Coumarin Antagonist of Chemokine – like factor 1 with oral Anti-asthma activity in mice. J Med Chem 2010, 53 (4), 1741–1754.
20.Hai Xue, Xiaofan Lu, Purong Zheng, Li LIU, Chunyan Han, Jinping HU, Zijie Liu, Tao MA, Yan LI, Lin WANG , Zhiwei CHEN*, Gang LIU*, Highly suppressing wide type HIV-1 and Y181C mutation by 10-Chloromethyl-11-Demethyl-12-oxo calanolide A with druggable profile. J Med Chem 2010, 53, 1397–1401.
21.Leilei Zhang, Yu Yan, Zijie Liu, Abliz Zeper, Gang Liu*, Identification of Peptide Substrate and Small Molecule Inhibitors of Testis-specific Serine/Threonine Kinase1 (TSSK1) By the Developed Assays, J Med Chem 2009, 52, 4419-4428.
22.Fa Zhang, Wei Zhang, Yan Zhang,  Dennis P. Curran, and Gang Liu*, Synthesis and Applications of Light-Fluorous Glycosyl Donor, J Org Chem 2009, 74 (6), 2594-2597.
23.Tao MA, Li LIU, Hai XUE, Li LI, Chunyan HAN, Lin WANG, Zhiwei CHEN, Gang LIU*, The Chemical Library and Structure-Activity Relationship of Calanolide-A Analogues against HIV-1, J Med Chem 2008, 51, 1432–1446.
24.Xuqin Li, Junli Yu, Song Xu, Nan Wang, Hongzhen Yang, Zheng Yan, Guifang Cheng, Gang Liu*, Chemical Conjugation of Muramyl Dipeptide and Paclitaxel to Explore the Combination of Immunotherapy and Chemotherapy for Cancer, Glycoconj J 2008, 25: 415–425.
25.Tao MA, Qi GAO, Zhiwei Chen, Lin WANG, Gang LIU*, Chemical Resolutions of (±)-Calanolide A, (±)-Cordatolide A and Their 11-Demethyl Derivatives, Bioorg. & Med. Chem. Letts. 2008,18, 1079–1083.
26.Tian-Ming Yang, Gang Liu*, Solution-Phase Parallel Synthesis of 3-Substituted Indolin-2-ones, J Comb Chem 2007, 9, 86-95.
27.Hongbo Hu, Li Li , Richard Y. Kao, Binbin Kou, Zhanguo Wang, Liang Zhang, Huiyuan Zhang, Zhiyong Hao, Wayne H. Tsui, Anping Ni, Lianxian Cui, Baoxing Fan, Feng Guo, Shuan Rao, Chengyu Jiang, Qian Li, Manji Sun, Wei He*, Gang Liu*, Screening and Identification of Linear B-cell Epitopes and Entry Blocking Peptide of Severe Acute Respiratory Syndrome (SARS) Associated Coronavirus Using Synthetic Overlapping Peptide Library, J Comb Chem 2005, 7, 648-656.
28.Hong-Zhen Yang, Song Xu, Xue-Yan Liao, Suo-De Zhang, Zheng-Lun Liang, Bai-He Liu, Jin-Ye Bai, Chao Jiang, Jian Ding, Gui-Fang Cheng*, Gang Liu*, A novel immunostimulator, N2-[a-O-benzyl-N-(acetylmuramyl)-L-alanyl-D-isoglutaminyl]-N6-trans-(m-nitrocinnamoyl)-L-lysine (MDP-C), and its adjuvancy on the hepatitis B surface antigen, J Med  Chem 2005, 48, 5112-5122.