張永輝，清華大學長聘研究員、博士生導師、清華−北大生命聯合中心及人腦保護高精尖創新中心研究員，2019年作為10位青年才俊之一榮獲第六屆“樹蘭醫學青年獎”。1996年在淮海工學院獲化學工程學士學位、1999年大連理工大學獲應用化學碩士學位，2002年中科院上海有機化學研究所獲有機化學博士學位。2002-2012年美國伊利諾大學香槟分校博士後，研究科學家。2013年入職清華大學藥學院研究員。張永輝研究員長期從事（類）膽固醇代謝領域的藥學研究工作，主持國家重點研發項目、國家自然科學基金面上項目多項，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.等國際頂尖刊物上發表了研究論文52篇，授權專利11件。

教育工作背景

2019-迄今        清華大學藥學院長聘研究員

2016-2018       清華大學藥學院副教授（tenure-track）

2013-2016       清華大學醫學院藥學系研究員、博士生導師

2013-迄今        2011生物治療協同創新中心研究員

2006-2013       高級研究科學家，伊利諾大學香槟分校化學系

2003-2006       博士後助理，藥物化學方向，伊利諾大學香槟分校 (導師：Eric Oldfield)

2003                 部門主管，美國晟康公司上海分公司

1999-2002       博士, 有機化學方向，中科院上海有機化學研究所 (導師：袁承業院士)

1996-1999       碩士, 應用化學方向，大連理工大學 (導師：宋東明教授)

1992-1996      本科，化學工程方向, 淮海工學院

擔任的學術兼職

起止年月	名 稱	職務/職稱
2003.03-至今	美國化學學會	常規會員
2017.01-至今	江蘇省免疫代謝重點實驗室	學術委員會委員
2017.03-至今	江蘇省臨床免疫學重點實驗室	學術委員會委員
2017.04-至今	中國抗癌協會整合腫瘤學分會	委員會委員
2017.06-至今	北京藥學會	藥物化學生物學專業委員
2013.01-至今	Journal of Medicinal Chemistry、ACS Medicinal   Chemistry Letter 等	審稿人
2012.01-至今	中國國家自然科學基金化學部/醫學部	項目評審人

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. （*通訊作者）該工作被多家新聞媒體報道。兩次被Faculty 1000推薦。被《細胞》長文推薦，被《自然-免疫學綜述》報道。

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. （*通訊作者）該工作被Immunity評價會推動gamma delta T細胞的臨床應用。

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. （*通訊作者）

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. 

為本文的共同一作兼通訊作者，該工作先後被美國國立衛生研究院NIH、 《自然綜述-藥物發現》、《科學商務交流》（SciBX）報道

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推薦文章，PNAS評述文章，被雅虎、每日科學等媒體報道

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
*為本文的通訊作者, 被選為該期刊6月份封面文章, 被編輯在In This Issue 重點介紹.

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.

被選為 “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《化學與工程新聞》報道; Faculty 1000 推薦文章, 被美聯社等媒體報道，先導藥物被諾華譽為“理想的臨床抗癌候選藥物”。

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《化學與工程新聞》報道

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通訊作者)

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結構基礎，糾正了數１０年的學術謬誤

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 推薦文章

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.

專利

(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.