杰出校友张永辉（1996届化工专业毕业生）-环境与化学工程学院

张永辉，清华大学长聘研究员、博士生导师、清华−北大生命联合中心及人脑保护高精尖创新中心研究员，2019年作为10位青年才俊之一荣获第六届“树兰医学青年奖”。1996年在淮海工学院获化学工程学士学位、1999年大连理工大学获应用化学硕士学位，2002年中科院上海有机化学研究所获有机化学博士学位。2002-2012年美国伊利诺大学香槟分校博士后，研究科学家。2013年入职清华大学药学院研究员。张永辉研究员长期从事（类）胆固醇代谢领域的药学研究工作，主持国家重点研发项目、国家自然科学基金面上项目多项，迄今在Cell、Immunity、Science Translational Medicine、PNAS 、Sci. Trans. Med、PNAS、JACS、Angew. Chem、J.Med. Chem、Chem. Biol、ACS Med.Chem. Lett.等国际顶尖刊物上发表了研究论文52篇，授权专利11件。

教育工作背景

2019-迄今清华大学药学院长聘研究员

2016-2018 清华大学药学院副教授（tenure-track）

2013-2016 清华大学医学院药学系研究员、博士生导师

2013-迄今 2011生物治疗协同创新中心研究员

2006-2013 高级研究科学家，伊利诺大学香槟分校化学系

2003-2006 博士后助理，药物化学方向，伊利诺大学香槟分校 (导师：Eric Oldfield)

2003 部门主管，美国晟康公司上海分公司

1999-2002 博士, 有机化学方向，中科院上海有机化学研究所 (导师：袁承业院士)

1996-1999 硕士, 应用化学方向，大连理工大学 (导师：宋东明教授)

1992-1996 本科，化学工程方向, 淮海工学院

担任的学术兼职

起止年月	名称	职务/职称
2003.03-至今	美国化学学会	常规会员
2017.01-至今	江苏省免疫代谢重点实验室	学术委员会委员
2017.03-至今	江苏省临床免疫学重点实验室	学术委员会委员
2017.04-至今	中国抗癌协会整合肿瘤学分会	委员会委员
2017.06-至今	北京药学会	药物化学生物学专业委员
2013.01-至今	Journal of Medicinal Chemistry、ACS Medicinal Chemistry Letter 等	审稿人
2012.01-至今	中国国家自然科学基金化学部/医学部	项目评审人

主要研究成果

1. Xia, Y., Xie, Y., Yu, Z., Xiao, H., Jiang, G., Zhou, X., Yang, Y., Li, X., Zhao, M., Li, L., Zheng, M., Han, S., Zong, Z., Meng, X., Deng, H., Ye, H., Fa, Y., Wu, H., Oldfield, E., Hu, X., Liu, W*., Shi, Y*., Zhang, Y*. The mevalonate pathway is a druggable target for vaccine adjuvant discovery. Cell, 2018, 175, 1059-1073. （*通讯作者）该工作被多家新闻媒体报道。两次被Faculty 1000推荐。被《细胞》长文推荐，被《自然-免疫学综述》报道。

2. Yang, Y., Li, L., Zhou, X., Duan, J., Liu, W., Chen, C., Wang, L., Li, X., Cai, N., Yuan, L., Chen, J., Kang, N., Malwal, S.R., Shi, Y., Oldfield, E*., Guo, R-T*., Zhang, Y*. A structural change in butyrophilin upon phosphoantigen binding underlies phosphoantigen-mediated Vγ9Vδ 2 T cell activation. Immunity, 2019, 50, 1043-1053. （*通讯作者）该工作被Immunity评价会推动gamma delta T细胞的临床应用。

3. Malwal, S.R., Gao, J., Hu, X., Yang, Y., Liu, W., Huang, J., Ko, T-Z., Li, L., Chen, C., O’Dowd, B., Khade, R., Zhang, Y., Zhang, Y*., Oldfield, E*., Guo, R-T*. Catalytic role of conserved asparagine, glutatmine, serine, and tyrosine residues in isoprenoid biosynthesis enzymes. ACS Catalysis. 2018, 8, 4299-4312.

4. Wang, Y., Chen, C-C., Yang, Y., Liu, W., Ko, T-P., Shang, N., Hu, X., Xie, Y., Huang, J-W., Zhang,Y*., Guo, R*. Structural insight into a novel indole prenyltransferase in hapalindole-type alkaloid biosynthesis. Biochem. Biphys. Res. Commun. 2018, 495, 1782-1788.

5. Chen, C-C., Hu, X., Tang, X., Yang, Y., Ko, T-Z., Gao, J., Zheng, Y., Huang, J., Yu, Z., Li, L., Han, S., Cai, N., Zhang, Y*., Liu, W*., Guo, R-T*. Crystal structure of a new class of cyclases which catalyze Cope rearrangement. Angew. Chem. Int. Ed. 2018, 57, 15060-15064.

6. Zhou, X., Gu, Y., Xiao, H., Kang, N., Xie, Y., Zhang, G., Shi, Y., Hu, X., Oldfield, E., Zhang, X*., Zhang, Y*. Combining Vγ9Vδ2 T cells with a lipophilic bisphosphonate efficiently kills activated hepatic stellate cells. Front. Immunol. 2017, 8, 1381.

7. Xia, Y.; Liu, Y-L.; Xie, Y.; Zhu, W.; Guerra, F.; Shen, S.; Yeddula, N.; Fischer, W.; Low, W.; Zhou, X.; Zhang, Y*.; Oldfield, E*.; Verma, I. M*. A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin. Sci. Trans. Med. 2014，263ra261. （*通讯作者）

8. Zhu, W¹.； Zhang, Y¹*.; Sinko, M.; Hensler, M.; Olson, J. et. al. Antibacterial drug leads targeting isoprenoid biosynthesis. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 123-128.

为本文的共同一作兼通讯作者，该工作先后被美国国立卫生研究院NIH、《自然综述-药物发现》、《科学商务交流》（SciBX）报道

9. Zhang, Y.; *, Zhu, W.; Liu, Y.; Wang, H.; Wang, K.; et. al. Chemo-Immunotherapeutic antimalarials targeting isoprenoid biosynthesis. ACS Med. Chem. Lett. 2013, 4, 423-426.

10.No, J.H.;¹ Dossin, F. M.;¹ Zhang, Y.;¹ Liu, Y-L.; Ku, M-J.; Zhu, W. et. al. Lipophilic analogs of zoledronate and risedronate inhibit Plasmodium geranylgeranyl diphosphate synthase and exhibit anti-malaria activity. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 4058-4063.
¹共同一作, Faculty 1000推荐文章，PNAS评述文章，被雅虎、每日科学等媒体报道

11. Zhang, Y*.; Lin, F-Y.; Li, K.; Zhu, W.; Liu, Y.L.; Cao, R.; Pang, R.; Lee, E.; Hensler, M.; Wang, K.; Mitchell, D.; Nizet, V.; Oldfield, E. HIV-1 integrase inhibitors inspired antibacterials targeting isoprenoid biosynthesis. ACS Med. Chem. Lett. 2012, 3, 402-406
*为本文的通讯作者, 被选为该期刊6月份封面文章, 被编辑在In This Issue 重点介绍.

12. Lin, F.;¹ Zhang, Y.;¹ Hensler, M.; Liu, Y.; Chow, O. A.; Zhu, W.; Wang, K.; Pang, R.; Thienphrapa, W.; Nizet, V.; Oldfield, E. Dual dehydrosqualene/squalene synthase inhibitors: Leads for innate immune system based therapeutics. ChemMedChem. 2012, 7, 561-564. (¹共同一作)

13. Zhang, Y.; Cao R.; Yin, F.; Lin, F.Y.; Wang, H.; Krysiak, K.; No, J.H.; Mukkamala, D.; Houlihan, K.; Li, J.; Morita, C.T.; Oldfield, E. Lipophilic pyridinium bisphosphonates: potent γδT cell stimulators. Angew. Chem. Int. Ed. 2010, 49, 1136-8.

被选为 “hot paper”

14. Zhang, Y.; Cao, R.; Yin, F.; Hudock, M.P.; Guo, R.T.; Krysiak, K.; et al. Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-ray and NMR investigation. J. Am. Chem. Soc. 2009, 131, 5153-62.
被《化学与工程新闻》报道; Faculty 1000 推荐文章, 被美联社等媒体报道，先导药物被诺华誉为“理想的临床抗癌候选药物”。

15. Cao, R.;¹ Zhang, Y.;¹ Mann, F.M.; Huang, C.; Mukkamala, D.; Hudock, M.P.; Mead, M.E.; Prisic, S.; Oldfield, E. Diterpene cyclases and the nature of the isoprene fold. Proteins. 2010, 78, 2417-32.
¹共同一作, 被《化学与工程新闻》报道

16. ¹Singh, A.P.; Zhang, Y, No, J.H.; Docampo, R.; Nussenzweig, V.; Oldfield, E. Lipophilic bisphosphonates are potent inhibitors of Plasmodium liver-stage growth. Antimicrob. Agents Chemother. 2010, 54, 2987-93. (¹通讯作者)

17. Zhang, Y.; Hudock, M. P.; Krysiak, K.; Cao, R.; Bergan, K.; Yin, F.; Leon, A.; Oldfield, E., Activity of sulfonium bisphosphonates on tumor cell lines. J. Med. Chem. 2007, 50, 6067-79.

18. Chen, C.;¹ Hudock, M. P.;¹ Zhang Y.;¹ Guo, R. T.; Cao, R.; No, J. H.; Liang, P. H.; Ko, T. P.; Chang, T. H.; Chang, S. C.; Song, Y.; Axelson, J.; Kumar, A.; Wang, A. H.; Oldfield, E., Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: a crystallographic and computational investigation. J. Med. Chem. 2008, 51, 5594-607. (¹共同一作)

19. Zhang, Y.; Song, Y.; Yin, F.; Broderick, E.; Siegel, K.; Goddard, A.; Nieves, E.; Pasa-Tolic, L.; Tanaka, Y.; Wang, H.; Morita, C. T.; Oldfield, E., Structural studies of Vgamma2Vdelta2 T cell phosphoantigens. Chem. Biol. 2006, 13, 985-92.
首次揭示了天然膦抗原的结构基础，纠正了数１０年的学术谬误

20. Zhang, Y.; Leon, A.; Song, Y.; Studer, D.; Koscielski, L. A.; Oldfield, E., Activity of nitrogen-containing and non-nitrogen-containing bisphosphonates on tumor cell lines. J. Med. Chem. 2006, 49, 5804-14.

21. Zhang, Y.; Xu, C.; Li, J.; Yuan, C. Enzymatic synthesis of optically active δ-hydroxy-β-ketoalkanephosphonates. Tetrahedron: Asymmetry 2003, 14, 63-70.

22. Zhang, Y.; Li, J.; Yuan, C. Enzymatic synthesis of optically active trifluoromethylated 1- and 2-hydroxyalkanephosphonates. Tetrahedron 2003, 59, 473-9.

23. Zhang, Y.; Li, J.; Wang, K.; Yuan, C. Lipases-catalyzed alcoholysis for the preparation of chiral 1- or 2-hydroxyalkanephosphonates. Chi. J. Chem. 2003, 21, 4-6.

24. Zhang, Y.; Xu, C.; Li, J.; Yuan, C. Candida rugosa lipase-catalyzed kinetic resolution of hydroxyalkanephosphonates. Chi. J. Chem. 2003, 21, 883-92.

25. Zhang, Y.; Li, Z.; Yuan, C. Biocatalytical kinetic resolution of hydroxyalkanephosphonates. Phosphorus, Sulfur, Silicon Relat. Elem. 2002, 177, 2201-2.

26. Zhang, Y.; Li, Z.; Yuan, C. Candida rugosa lipase-catalyzed enantio-selective hydrolysis in organic solvents. Convenient preparation of optically pure 2-hydroxy-2-arylethanephosphonates. Tetrahedron. Lett. 2002, 43, 3247-9.

27. Zhang, Y; Yuan, C.; Li, Z. Studies on organophosphorus compounds. 115. Kinetic resolution of hydroxyalkanephosphonates catalyzed by Candida antarctica lipase B in organic media. Tetrahedron 2002, 58, 2973-8.

28. Zhang, Y.; Cao, R.; Hudock, M-P.; Wilson, S-R.; Oldfield, E. [2-(Dimethylsulfonio)-1-hydroxy-1-phosphonoethyl]phosphonate monohydrate. Acta Crystallographica, Section E: Structure Reports Online 2006, E62, o1006-8.

29. Gao, J., Ko, TP., Chen, L., Malwal, SR., Zhang, J., Hu, X., Qu, F., Liu, W., Huang, J.W., Cheng, Y., Yang, Y., Zhang, Y., Oldfield, E., Guo, R*. “Head-to-middle” and “head-to-tail” cis-prenyl transferase: structure of isosesquilavandulyl diphosphate synthase. Angew. Chem. Int. Ed. 2018, 57, 683-687.

30. Chen, Y., Zhang, Y., Jiang, Y., Qin, F., Zhang, Y., Fu, L., He, G*. Integrated bioinformatics, computational and experimental methods to discover novel Raf/extracellular signal regulated kinase (ERK) dual inhibitors against breast cancer cells. Eur. J. Med. Chem. 2017, 127, 997-1011.

31. Chen, X., Wu, Y., Yang, T., Wei, M., Wang, Y., Deng, X., Shen, C., Li, W., Zhang, H., Xu, W., Guo, L., Zeng, Y., Zhang, Y., Wang, Z., Yang, J*. Salidroside alleviates cachexia symptoms in mouse models of cancer cachexia via activating m-TOR signaling. J. Cachexia. Sarcopenia Muscle, 2016, 7, 225-232.

32. Wang, Y., BenZ F., Wu, Y., Chen, Y., Li, H., Zhang, Y., Zhang, R., Yang, J*. Structural insights into the pharmacophore of vinca domain inhibitors of microtubules. Mol. Pharmacol. 2016, 89, 233-242.

33. Cheng, L., Ge, M., Lan, Z., Chi, W., Kuang, W., Sun, K., Zhao, X., Liu, Y., Feng, Y., Huang, Y., Luo, M., Li, L., Zhang, B., Hu, X., Xu, L., Liu, X., Huo, Y., Deng, H., Yang, J., Xi, Q., Zhang, Y., Siegenthaler, JA., Chen, L*. Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch. Toxicol. 2018, 92, 469-485.

34. Chen, Y.; Wang, S.; Zhang, L.; Xie, T.; Song. S.; Huang, J.; Zhang, Y.; Ouyang, L.; Liu, B*. Identification of ULK1 as a novel biomarker involved in miR-4487 and miR-595 regulation in neuroblastoma SH-SY5Y cell autophagy. Sci. Rep. 2015 Jul 17; 5:11035. doi: 10.1038/srep11035.

35. Fu, LL.; Tian, M.; Li, X.; Li, JJ, Huang, J.; Ouyang, L.; Zhang, Y.; Liu, B. Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery. Oncotarget 2015, 6, 5501-16.

36. Fu, L.; Zhang, S.; Zhang, L.; Tong, X.; Zhang, Y.; Ouyang, L, Liu, B.; Huang, J. Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer. Oncotarget 2015, 6, 8071-88.

37. Liu, B.; Fu, L.; Zhang, C.; Zhang, Y.; Ouyang, L.; He, G.; Huang, J. Computational design, chemical synthesis, and biological evaluation of a novel ERK inhibitor (BL-E1001) with apoptosis-inducing mechanisms in breast cancer. Oncotarget 2015, 6, 6762-75.

38. Span, I.; Wang, K.; Wang, W.; Zhang, Y.; Bacher, A.; Eisenreich, W.; Li, K.; Schulz, C.; Oldfield, E.; Groll. M. Discovery of acetylene hydratase activity of the iron-sulphur protein IspH. Nat. Comm. 2012; 3:1042.

39. Xia, Y.; Yeddula, N.; Leblanc, M.; Ke, E.; Zhang, Y.; Oldfield, E.; Verma, I.M. Reduced cell proliferation by IKK2 depletion in a mouse lung-cancer model. Nat. Cell. Bio. 2012, 14, 257-265.

40. Lin, FY.; Liu, C-I.; Liu, Y-L.; Zhang, Y.; Wang, K.; Jeng, W.Y.; Ko, TP.; Cao, R.; Wang, A.H.; Oldfield, E. Mechanism of action and inhibition of dehydrosqualene synthase. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 21337-42.

41. Ramos, IB.; Miranda, K.; Pace, DA.; Verbist, KC.; Lin, FY.; Zhang Y.; Oldfield, E.; Machado EA, De Souza, W.; Docampo, R. Calcium- and polyphosphate-containing acidic granules of sea urchin eggs are similar to acidocalcisomes, but are not the targets for NAADP. Biochem. J. 2010, 429, 485-495.

42. Wang, K.; Wang, W.; No, J-H.; Zhang, Y.; Oldfield, E. Inhibition of the Fe₄S₄-Cluster-Containing Protein IspH (LytB): Electron paramagnetic resonance, metallacycles, and mechanisms. J. Am. Chem. Soc. 2010, 132, 6719-27.
Faculty 1000 推荐文章

43. Guo, R. T.; Cao, R.; Liang, P. H.; Ko, T. P.; Chang, T. H.; Hudock, M. P.; Jeng, W. Y.; Chen, C. K.; Zhang, Y.; Song, Y.; Kuo, C. J.; Yin, F.; Oldfield, E.; Wang, A. H., Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases. Proc. Natl. Acad. Sci. U.S. A. 2007, 104, 10022-7.

44. Yin, F.; Cao, R.; Goddard, A.; Zhang, Y.; Oldfield, E., Enthalpy versus entropy-driven binding of bisphosphonates to farnesyl diphosphate synthase. J. Am. Chem. Soc. 2006, 128, 3524-5.

45. Mao, J.; Mukherjee, S.; Zhang, Y.; Cao, R.; Sanders, J.; Song, Y.; Zhang, Y.; Meints, G.; Gao, YG.; Mukkamala, D.; Hudock, MP.; Oldfield, E. Solid-state NMR, crystallographic, and computational investigational of bisphosphonates and farnesyl diphosphate synthase-bisphosphonate complexes. J. Am. Chem. Soc. 2006, 128, 14485-97.

46. Sanders, J-M.; Song, Y.; Chan, Julian M. W.; Zhang, Y.; Jennings, S.; Kosztowski, T.; Odeh, S.; Flessner, R.; Schwerdtfeger, C.; Kotsikorou, E.; Meints, G-A.; Gomez, A-Ortiz.; Gonzalez-Pacanowska, D.; Raker, A-M.; Wang, H.; van Beek, E-R.; Papapoulos, S-E.; Morita, C-T.; Oldfield, E. Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption. J. Med. Chem. 2005, 48, 2957-63.

47. Wouters, J.; Yin, F.; Song, Y.; Zhang, Y.; Oudjama, Y.; Stalon, . Droogmans, L.; Morita, C-T.; Oldfield, E. A Crystallographic investigation of phosphoantigen binding to isopentenyl pyrophosphate/dimethylallyl pyrophosphate isomerase. J. Am. Chem. Soc. 2005, 127, 536-37.

48. Song, Y.; Zhang, Y.; Wang, H.; Raker, A.; Sanders, J.; Broderick, E; Clark, A.; Morita, C.; Oldfield, E. Synthesis of chiral phosphoantigens and their activity in T cell stimulation. Bioorg. Med. Chem. Lett. 2004, 14, 4471-7.

49. Xu, C.; Zhang, Y.; Yuan, C. A new and convenient route to optically active 2-phosphoryl-3-oxo-5-alkyl/-aryltetrahydrofurans and their reactions. Eur. J. Org. Chem. 2004, 10, 2253-62.

50. Xu, C.; Zhang, Y.; Yuan, C. A chemoenzymatic approach to optically active 5-hydroxy-3-oxocarboxylates. Synlett 2004, 3, 485-8.

51. Wang, K.; Zhang, Y.; Yuan, C. Enzymatic synthesis of phosphocarnitine, phosphogabob and fosfomycin. Org. Biomol. Chem. 2003, 1, 3564-9.

52. Yuan, C.; Xu, C.; Zhang, Y. Enzymatic synthesis of optically active 1- and 2-aminoalkanephosphonates. Tetrahedron 2003, 59, 6095-102.

专利

(1)	Zhang, Y., Xia, Y., Xie, Y., Yu, Z., Zhou, X., Li, X., Li, L., Gao, K., Wang, K. Mevalonate pathway inhibitors as highly-effective vaccine adjuvants. PCT Int. Appl. (2017), WO 2017041720 A1 20170316.
(2)	Zhang, Y., Zhou, X., Xiao, H., Xia, Y. Mevalonate pathway inhibitors and pharmaceutical compositions thereof. 2017, CN 201710962422.0.
(3)	Zhang, Y., Zhou, X., Xiao, H. Application of adoptively transferred Vγ9Vδ2 T cells and their agonists in the treatment of liver fibrosis, cirrhosis and liver cancer. 2017, CN 201710952624.7.
(4)	Zhang, Y., Li, L., Xie, Y. Highly potent and stable Vγ9Vδ2 T cell agonists. 2017, CN 201710943685.7.
(5)	Zhu, W., Lindert, S., Zhang, Y., Sinko, W., Li, Kai., Mccammon, James A., Oldfield, E. Antibacterial compounds targeting isoprenoid biosynthesis. U.S. Pat. Appl. Publ. (2016), US 20160039857 A1 20160211.
(6)	Vema, Inder M., Zhang, Y., Oldfield, E., Xia, Y. Lipophilic bisphosphonates and methods of use. PCT Int. Appl. (2016), WO 2016081281 A1 20160526.
(7)	Oldfield, E., Wang, K., Wang, W., Zhang, Y. Enzyme inhibiting compounds and methods. 2013, US 8609638 B2 20131217.
(8)	Oldfield, E., Wang, K., Wang, W., Zhang, Y. Preparation of alkynyl diphosphates as Enzyme inhibiting compounds and methods. PCT Int. Appl. (2011), WO 2011044505 A2 20110414.
(9)	Oldfield, E., Zhang, Y. Bisphosphonate compounds with enhanced potency for multiple targets including FPPS, GGPPS, and DPPS and use in treating various diseases. U.S. Pat. Appl. Publ. (2008), US 20080255070 A1 20081016.
(10)	Oldfield, E., Song, Y., Zhang, Y., Sanders, John M. α-Hydroxy bisphosphonates containing non-nitrogen cationic phosphonium, arsonium and sulfonium centers as antitumor and antibacterial agents. PCT Int. Appl. (2007), WO 2007109585 A2 20070927.
(11)	Sanders, John M., Song, Y., Chan, Julian M.W., Oldfield, E., Zhang, Y. Bisphosphonate compounds and methods for bone resorption diseases, cancer, bone pain, immune disorders, and infectious diseases. PCT Int. Appl. (2006), WO 2006039721 A2 20060413.