隨著人口老齡化的加劇，整個(gè)社會(huì)對(duì)更有效的藥物治療的需求隨之上升。然而，隨著制藥行業(yè)對(duì)于小分子藥物可成藥的靶向目標(biāo)的不斷篩選，發(fā)現(xiàn)新的靶向目標(biāo)也越來(lái)越難。同時(shí)，大分子藥物、尤其是蛋白質(zhì)藥物的崛起為新藥的開(kāi)發(fā)提供了巨大的機(jī)會(huì)。目前，越來(lái)越多的大分子藥物已被批準(zhǔn)，其中有相當(dāng)一部分治療的正是目前小分子藥物無(wú)法治療的疾病。然而，與其迅速的增長(zhǎng)相比，一些內(nèi)在的挑戰(zhàn)仍然限制大分子藥物的發(fā)展前景。本實(shí)驗(yàn)室的研究致力于解決大分子藥物研發(fā)過(guò)程中的一些關(guān)鍵性的挑戰(zhàn)，從而研制出創(chuàng)新性的生物類藥物。本實(shí)驗(yàn)室的研究處于交叉學(xué)科的領(lǐng)域，其很大程度上依賴于對(duì)于各種知識(shí)和技能的綜合，如分子生物學(xué)、化學(xué)合成、蛋白質(zhì)工程和生物偶聯(lián)技術(shù)。本實(shí)驗(yàn)室的工作根植于基礎(chǔ)的生物和化學(xué)知識(shí)；從而實(shí)現(xiàn)由科學(xué)發(fā)現(xiàn)向臨床應(yīng)用的轉(zhuǎn)化。目前的科研項(xiàng)目包含“從實(shí)驗(yàn)到臨床”的藥物研究，主要集中在采用蛋白為基礎(chǔ)的新一代大分子藥物治療癌癥、免疫系統(tǒng)疾病、糖尿病等等。具體而言，本實(shí)驗(yàn)室主要致力于以下幾個(gè)方面的研究：
。傳統(tǒng)的單克隆抗體研發(fā)已無(wú)法滿足現(xiàn)今對(duì)于新型抗體藥物不斷增長(zhǎng)的需求。并且，以結(jié)合強(qiáng)度為準(zhǔn)則的抗體篩選方法無(wú)法產(chǎn)生有特定功能的抗體藥物，比如具有激動(dòng)劑或反激動(dòng)劑活性的抗體、或者離子通道阻滯劑及酶抑制劑。本課題組利用合成化學(xué)的多樣性，大大拓展了傳統(tǒng)抗體在抗原識(shí)別區(qū)對(duì)于有限的20種天然氨基酸官能團(tuán)的依賴，以簡(jiǎn)單普適的方法獲得新型的功能性抗體。
。很多重要的藥物靶點(diǎn)都存在于細(xì)胞內(nèi)部，其中包括攜帶突變的基因和功能錯(cuò)誤的蛋白。盡管蛋白質(zhì)、DNA和RNA可以有效的作用于細(xì)胞內(nèi)的藥物靶點(diǎn)并調(diào)節(jié)其功能，但是細(xì)胞膜阻止了大分子藥物對(duì)這類藥物靶點(diǎn)的接觸，從而使大分子藥物不能發(fā)揮其在細(xì)胞內(nèi)的作用。本實(shí)驗(yàn)室模仿自然界中最有效的大分子胞內(nèi)傳遞系統(tǒng)——病毒，設(shè)計(jì)了有效的組織特異性胞內(nèi)蛋白傳遞系統(tǒng)。借由此系統(tǒng)，也可以實(shí)現(xiàn)有效的小分子藥物及核酸類藥物的胞內(nèi)傳遞。
。下一代抗體藥物（NGA）是以抗體修飾為基本的新型藥物類型。在未來(lái)十年內(nèi)，NGA被預(yù)測(cè)會(huì)得到長(zhǎng)足的發(fā)展并在抗體藥物的市場(chǎng)上占到舉足輕重的地位。其中，多功能性抗體可以利用藥物之間的協(xié)同作用，也可以開(kāi)發(fā)新的治療機(jī)理，更是為新型抗體藥物的開(kāi)發(fā)提供了一個(gè)廣闊的平臺(tái)。本實(shí)驗(yàn)室采用蛋白融合、特異性偶聯(lián)等技術(shù)開(kāi)發(fā)多種多功能性抗體。
發(fā)明了以單個(gè)蛋白質(zhì)為內(nèi)核、生物相容性的高分子為外殼的蛋白－高分子納米復(fù)合體（單蛋白納米膠囊），并以此提高了蛋白的穩(wěn)定性，延長(zhǎng)了蛋白的循環(huán)時(shí)間以及實(shí)現(xiàn)了可控的表面功能性。
圖二、可降解BMP-2納米膠囊以及其在骨再生手術(shù)中的應(yīng)用。BMP-2納米膠囊可以持續(xù)釋放出BMP-2,并且獲得更高的成骨質(zhì)量
優(yōu)秀研究生銀獎(jiǎng), 美國(guó)材料學(xué)會(huì)(MRS)，2013年
研究生論文獎(jiǎng), 加州大學(xué)洛杉磯分校，2012年
代表論文
1. H. Tian?; J. Du? (Co-author with equal contribution); J. Wen; Y. Liu; S. R. Montgomery; T. P. Scott; B. Aghdasi; C. Xiong; A. Suzuki; T. Hayashi; M. Ruangchainikom; K. Phan; G. Weintraub; A. Raed; S. S. Murray; M. D. Daubs; X. Yang; X.-B. Yuan; J. C. Wang; Y. Lu. Growth-Factor Nanocapsules That Enable Tunable Controlled Release for Bone Regeneration. ACS Nano 2016 in press
2. T. Liu?; J. Du? (Co-author with equal contribution); X. Luo; P. G. Schultz; F. Wang. Homogeneously modified immunoglobulin domains for therapeutic application. Curr. Opin. Chem. Biol. 2015, 28, 66-74.
3. J. Du; J. Jin; Y. Liu; J. Li; T. Tokatlian; Z. Lu; T. Segura; X. Yuan; X. Yang; Y. Lu. Gold-Nanocrystal Enhanced Bioluminescent Nanocapsules. ACS Nano, 2014, 8, 9964-9969.
4. W. Wei?; J. Du? (Co-author with equal contribution); J. Li; M. Yan; Q. Zhu; X. Jin; X. Zhu; Z. Hu; Y. Tang; Y. Lu. Construction of Robust Enzyme Nanocapsules for Effective Organophosphate Decontamination, Detoxification and Protection. Advanced Materials, 2013, 25, 2212-2218.
5. Y. Liu?; J. Du? (Co-author with equal contribution); M. Yan; M. Y. Lau; J. Hu ; H. Han ; O. O. Yang ; S. Liang ; W. Wei ; H. Wang ; J. Li ; X. Zhu ; L. Shi; W. Chen ; C. Ji; Y. Lu. Biomimetic Enzyme Nanocomplexes and Their Use as Antidotes and Preventive Measures for Alcohol Intoxication. Nature Nanotechnology, 2013, 8, 187-192.
6. J. Du; J. Jin; M. Yan; Y. Lu. Synthetic Nanocarriers for Intracellular Protein Delivery. Current Drug Metabolism, 2012, 13, 82-92.
7. J. Du; C. Yu; D. Pan ; J. Li; W. Chen; M. Yan; T. Segura; Y. Lu. Quantum-Dot-Decorated Robust Transductable Bioluminescent Nanocapsules. J. Am. Chem. Soc. 2010, 132, 12780-12781.
8. M. Yan?; J. Du? (Co-author with equal contribution); Z. Gu; M. Liang; Y. Hu; W. Zhang; S. Priceman; L. Wu; Z. H. Zhou; Z. Liu; T. Segura; Y. Tang; Y. Lu. A novel intracellular protein delivery platform based on single-protein nanocapsules. Nature Nanotechnology, 2010, 5, 48-53.
9. J. Du; Z. Li; D.-M. Du; J. Xu. Improving enantioselectivity via rationally tuning electronic effects of catalysts in organocatalytic asymmetric Aldo reaction. ARKIVOC, 2008, 17, 145-156.
10. J. Du; Z. Li; D.-M. Du; J. Xu. Unexpected influence and its origin in rationally tuning the electronic effect of catalysts in the asymmetric borane reduction of ketones. J. Mol. Cat. A: Chemical, 2008, 284, 40-45.
11. Y. Cao; D. T. Rodgers; J. Du; I. Ahmad; E. N. Hampton; J. S. Y. Ma; M. Mazagova; S.-H. Choi; H. Y. Yun; H. Xiao; P. Yang; X. Luo; R. K. V. Lim; H. M. Pugh; F. Wang; S. A. Kazane; T. M. Wright; C. H. Kim; P. G. Schultz; T. S. Young. Design of Switchable Chimeric Antigen Receptor T Cells Targeting Breast Cancer. Angew. Chem. Int. Ed. 2016, in press
12. Y. Liu; J. Du; J.-S. Choi; K.-J. Chen; S. Hou; M. Yan; W.-Y. Lin; K. S. Chen; T. Ro; G. S. Lipshutz; L. Wu; L. Shi; Y. Lu; H.-R. Tseng; H. Wang. A High-Throughput Platform for Formulating and Screening Multifunctional Nanoparticles Capable of Simultaneous Delivery of Genes and Transcription Factors. Angew. Chem. Int. Ed. 2016, 55, 169–173.
13. D. T. Rodgers; M. Mazagova; E. N. Hampton; Y. Cao; N. S. Ramadoss; I. R. Hardy; A. Schulman; J. Du; F. Wang; O. Singer; J. Ma; V. Nunez; J. Shen; A. K. Woods; T. M. Wright; P. G. Schultz; C. H. Kim; T. S. Young. Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies. Proc. Nat. Acad. Sci. 2016, 113, E459–E468
14. X. Luo; T. Liu; Y. Wang; H. Jia; Y. Zhang; D. Caballero; J. Du; R. E. Wang; D. Wang; P. G. Schultz; F. Wang. An Epitope-Specific Respiratory Syncytial Virus Vaccine Based on an Antibody Scaffold. Angew. Chem. Int. Ed. 2015, 54, 14531–14534.
15. J. Wen; S. M. Anderson; J. Du; M. Yan; J. Wang; M. Shen; Y. Lu; T. Segura. Controlled Protein Delivery Based on Enzyme-Responsive Nanocapsules, Advance Materials, 2011, 23, 4549-4553.
16. J. Zhang; Y. Lei; A. Dhaliwal; Q. K. Ng; J. Du; M. Yan; Y. Lu; T. Segura. Protein-Polymer Nanoparticles for Nonviral Gene Delivery, Biomacromolecules, 2011, 12, 1006-1014.
17. J. Zhang; J. Du; M. Yan; A. Dhaliwal; J. Wen; F. Liu; T. Segura; Y. Lu. Synthesis of Protein Nano-Conjugates for Cancer Therapy. Nano Res., 2011, 4, 425-433.
18. Y. Peng; D. Jiang; L. Su; L. Zhang; M. Yan; J. Du; Y. Lu; Y. Liu; F. Zhou. Mixed Monolayers of Ferrocenylalkanethiol and Encapsulated Horseradish Peroxidase for Sensitive and Durable Electrochemical Detection of Hydrogen Peroxide, Anal. Chem., 2009, 81, 9985-9992.
19. X. Wang; J. Du; H. Liu; D.-M. Du; J. Xu. Effect of borane source on the enantioselectivity in the enantiopure oxazaborolidine-catalyzed asymmetric borane reduction of ketones. Hetero. Chem., 2007, 18, 740-746.
專利申請(qǐng)
Y. Lu; M. Yan; J. Du. Single protein nanocapsules for protein delivery with long-term effect. (WO 2010/104865 A3)
F. Wang; Y. Zhang; T. Liu; J. Du; Y. Wang; P. G. Schultz. Immunoglobulin fusion proteins and compositions thereof. (WO 2015/006744 A1)
F. Wang; J. Du; T. Young; P. G. Schultz. Constant region antibody fusion proteins and compositions thereof. (WO 2015/188135 A1)
