2016.08-2016.12

清华大学药学院

2016 秋季学期新闻简报

SCHOOL OF PHARMACEUTICAL SCIENCESTSINGHUA UNIVERSITY

NEWSLETTER

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SPS welcomes its first undergraduate cohort

Gates Foundation visits Beijing to discuss the development of GHDDI

Tsinghua University and the Scripps Research Institute collaborate on joint PhD program TPIC and GHDDI on exhibition during the Second National Entrepreneurship and Innovation Week in Shenzhen

SPS and Schrödinger jointly establish a Center of Excellence in Structure-Based Drug Discovery

Contents

The inaugural China-Japan "Tsing Yi" Forum successfully held

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ZU Liansuo lab publishes "Total Synthesis of Calophyline A" in Angew. Chem. Int. Ed.

WANG Jian lab publishes "Enantioselective Intermolecular Enamide-Aldehyde Cross-Coupling Catalyzed by Chiral N-Heterocyclic Carbenes" in J. Am. Chem. Soc.

XIAO Bailong lab publishes "Ion Permeation and Mechanotransduction Mechanisms of Mechanosensitive Piezo Channels" in Neuron

TANG Yefeng and LIU Gang lab publishes "Total Syntheses of Periconiasins A-E" in Angew. Chem. Int. Ed.

CHEN Ligong lab publishes "Inhibitor Discovery for the Human GLUT1 from Homology Modeling and Virtual Screening" in ACS Chemical Biology

LIAO Xuebin lab publishes "Nickel-Catalyzed Methylation of Aryl Halides with Deuterated Methyl Iodide" in Angew. Chem. Int. Ed.

LIAO Xuebin lab publishes "Transition-Metal-Free Synthesis of N-hydroxy Oxindoles by an Aza-Nazarov-Type Reaction Involving Azaoxyallyl Cations" in Angew. Chem. Int. Ed.

TAN Xu lab publishes "Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility" in Nature Genetics

Mission

News Highlights

Talent Development

Scientific Discovery

Translational Research

Conference and Forum

Collaboration and Development

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Mission

We are committed to advancing the understanding of unsolved diseases and innovating translational science, convert ing research discoveries and technological developments into new medicine and therapeutic approaches. We are dedicated to driving China's biomedical industry, while extending our reach and impact to improve human health on a global scale.

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Beijing, China, August 8th, 2016 - Professors and students celebrated the beginning of the 2016 Fall Semester at the School of Pharmaceutical Sciences (SPS), Tsinghua University, and welcomed the School's first cohort of undergraduate students since its establishment last December.

Prof. QIAN Feng, Associate Dean of SPS, delivered a welcome speech at the commencement ceremony. He particularly highlighted the unique programs offered by the School and the significant opportunities in the space of pharmaceutical sciences. Following his speech, the new students had an opportunity to ask questions and interact with the SPS professors, advisors and fellow students on program curriculum, course offerings, and student services and support.

SPS enrolled 23 undergraduate students from 15 provinces in China this year.

SPS welcomes its first undergraduate cohort

Gates Foundation visits Beijing to discuss the development of GHDDI

News Highlights

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Beijing, China, September 5th, 2016 - The Bill & Melinda Gates Foundation visited Beijing to continue discussing the development of the Global Health Drug Discovery Institute (GHDDI). This visit came after the initial meeting between the Beijing Municipal Government, Tsinghua University and the Gates Foundation in March this year.

For this meeting, Dr. Mark Suzman, Chief Strategy Officer and President, Global Policy & Advocacy of the Bill & Melinda Gates Foundation, and his delegation were received by SUI Zhenjiang, Deputy Mayor of Beijing Municipal Government, and CHENG Jianping, Executive Vice President of Tsinghua University.

During the meeting, Sui acknowledged the contribution and support from the Gates Foundation in developing and promoting GHDDI. He then elaborated on the new policies and approaches introduced by Beijing Municipal Government in preparation for the establishment of GHDDI.

GHDDI will be the first of its kind not-for-profit research organizaion in China funded by a unique Public-Private-Partnership (PPP) model, allowing the institute to leverage key strengths both from the public and the private sectors. Sui believed that this groundbreaking partnership could have far-reaching significance on the Gates Foundation's future projects with China.

On behalf of the Gates Foundation, Suzman spoke

highly of the expertise and support from Beijing Municipal Government and Tsinghua University in developing GHDDI. He said that the Foundation was very excited about the ongoing progress and would continue to provide full support to GHDDI's future development.

Cheng specifically pointed out that biomedical research was one of the key development areas of Tsinghua University towards becoming a world-class university. The establishment of GHDDI, through its innovative scientific research and translational platform, could significantly faciliate advancing Tsinghua's pharmaceutical and other related disciplines.

Background: At a meeting in Davos, Switzerland on January 22nd, 2016, QIU Yong, President of Tsinghua University, and Bill Gates, Co-chair of the Bill & Melinda Gates Foundation, agreed to co-found the Global Health Drug Discovery Institute, and signed a memorandum of understanding. On August 17th, 2016, GHDDI was officially registered in Beijing.

San Diego, U.S., September 24th, 2016 – The Scripps Research Institute (TSRI) and Tsinghua University signed an agreement for a joint PhD program. Tsinghua and TSRI will collaborate on a broad range of research and educational activities to tackle major diseases challenges.

During this meeting, the CEO of TSRI, Dr. Peter G. Schultz, welcomed the guests from Tsinghua. He gave an introduction about TSRI and a brief review of the collaborations already in progress. He was confident in the partnership with Tsinghua Universi ty, and bel ieved both inst i tut ions possess extraordinary strengths in the interface of chemistry and biology, leading to a natural partnership.

Tsinghua University and the Scripps Research Institute collaborate on joint PhD program

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"The new program will form a basis for much productive scientific collaboration and also provide a terrific training environment for the graduate students," Schultz said.

The program will leverage advantages and resources from both Tsinghua and TSRI to facilitate collaboration across various areas of biomedical sciences. The two institutions will develop a detailed program framework to deliver a creative and stringent doctoral training program. It will include cooperative admissions, dual-advisors from both institutions, laboratory rotations and a joint thesis defense. Student will be rewarded with a joint PhD degree granted by Tsinghua and TSRI upon completion of this program.

QIU Yong, President of Tsinghua University, believed that collaboration with TSRI would greatly accelerate the development

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Shenzhen, China, October 12th, 2016 - The Tsinghua Pharmaceutical Innovation Center (TPIC) and Global Health Drug Discovery Institute (GHDDI) made their official debut as the core exhibitions of the Second National Entrepreneurship and Innovation Week in Shenzhen.

TPIC is a biomedical innovation and entrepreneurial platform developed and supported by SPS. Together with collaborators from academia and various industry sectors in China and around the world, TPIC endeavors to explore innovative and sustainable models in translational research and entrepreneurial talent development.

GHDDI is partnered with and co-founded by the Bill & Melinda Gates Foundation and the Beijing Municipal Government, leveraging translational research and development capabilities to address unmet medical needs in global health.

The two were exhibited in the Shenzhen main venue from October 12th to 18th.

TPIC and GHDDI on exhibition during the Second National Entrepreneurship and Innovation Week in Shenzhen

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in drug discovery and talent cultivation at Tsinghua.

"Biomedical and pharmaceutical sciences are one of the key development areas of the University," Qiu said. "Tsinghua is committed to enhancing its overall capabilities in biomedical research to impact global pharmaceutical innovations and public health."

"The partnership with TSRI opened another chapter as SPS embarks on a journey of innovation and discovery." said DING Sheng, Dean of the School of Pharmaceutical Sciences, "We will work closely with collaborators at TSRI to catalyze new drug discovery and build a global ecosystem for pharmaceutical innovations."

After the signing ceremony, President Qiu toured around

the TSRI campus as well as the California Institute for Biomedical Research (Calibr), which was recently integrated into TSRI. He also discussed with Schultz about how to effectively enhance the collaborative work between Calibr and the Global Health Drug Discovery Institute (GHDDI) which is currently under development by Tsinghua University.

The Scripps Research Institute is one of the largest non-profit research institutes in the world. The institute has over 250 labs and 2,700 employees and graduate students. Many distinguished scientists are working here including two Nobel laureates, eighteen Members of the National Academy of Science or Engineering, and nine Members of the National Academy of Medicine.

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SPS and Schrödinger jointly establish a Center of Excellence in Structure-Based Drug Discovery

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Following the launching ceremony, China's Premier LI Keqiang visited the main venue, including the core exhibit ion area of Tsinghua University. Premier Li applauded the latest achievements of Tsinghua in scientific research and innovation while CHEN Xu, Chairperson of Tsinghua University Council, introduced each exhibition.

Shenzhen is China's major powerhouse for technology and innovation and served as the main venue of this year's event.

Beijing, China, October 18th, 2016 – Schrödinger, Inc. and School of Pharmaceutical Sciences have reached an agreement to establish a Center of Excellence (COE) in Structure-Based Drug Discovery at Tsinghua University. Under the terms of the agreement, Schrödinger will provide its computational chemistry software to the COE, and work with the faculty at Tsinghua University to create a curriculum for researchers at the University and throughout China on using Schrödinger's software solutions in drug discovery.

"We're honored to be chosen as the technology platform by Tsinghua University, a world renowned and distinguished institution," said Schrödinger's president, Dr. Ramy Farid. "Our platform has demonstrated successes in drug discovery programs, and we are excited to share our technology with our partners and researchers in China."

The COE will focus on developing the knowledge and expertise of Tsinghua researchers by providing training in the underlying theories of computational chemistry and the application of Schrödinger's simulation tools in the drug discovery process. Furthermore, under the terms of the agreement, Schrödinger and Tsinghua University may enter into research collaborations on projects of mutual interest.

"We are very happy to work with Schrödinger, the undisputed science and technology leader in this field," said Prof. DING Sheng, Dean of SPS of Tsinghua University. "We are very proud of the Center of Excellence – it supports the educational mission of Tsinghua University and together with our renowned structural biology capability will provide Chinese scientists with the tools to develop innovative medicines and therapeutic approaches to improve human health."

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Talent Development

Since the establishment of SPS in December 2015, we have been actively recruiting outstanding faculty members around the world. In 2016, 5 Principle Investigators (PI), and 1 overseas tenured professor have joined SPS. They are:

To date, we have built a core faculty team of 23 Principle Investigators, all with rich overseas reserch and working experiene. Over 70% faculty members are recognized with top national honors and international awards, such as the Thousand Talents Plan Professorship, the Changjiang Distinguished Professorship and the Youth Thousand Talents Plan Professorship. In 2016, Dr. HE Wei and Dr. RAO Yu were awarded the "National Science Foundation for Distinguished Young Scientists" and "Changjiang Distinguished Young Scholars" respectively.

SPS will contiue to expand its faculty team and research focus. Four PIs have confirmed to join the School in 2017, whose expertise spans across gene editing, pharmacogenomics, gene engineering and computational chemistry.

Sequencing Technology, Nano Devices, Bio-sensor, Single-molecule Detection, and Nano-pore Devices

Mass Spectrometry, Metabolic Analysis, Metabolic Mechanism of Disease, New Drug Target, and Precision Medicine

Adult Stem Cells, Regenerative Medicine, Digestive Diseases, and Abnormal Stem Cells

Macro/Biologics Drugs

Drug Screening, Target Identification,Aging Biology, Cell Death, and Age-related Diseases

Cancer Diagnosis and Treatment

BAI Jingwei PhD

HU Zeping PhD

WANG Xia PhD

David Huang PhD

DU Juanjuan PhD

WANG Gelin PhD

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WANG Jian's research group discovered a way to produce synthetic Chiral bonds. His paper "Enantioselective Intermolecular Enamide-Aldehyde Cross-Coupling Catalyzed by Chiral N-Heterocyclic Carbenes" was published in the Journal of American Chemical Society.

In his paper, the unprecedented N-heterocyclic carbene (NHC)-catalyzed intermolecular cross-coupling of enamides and aldehydes is described. Upon exposure of enamides to aldehydes in the presence of a NHC catalyst, catalytic C-C bond

formation occurs, providing highly enantioselective N-protected amines, bearing a quaternary carbon center, in good yields and with high enantioselectivities.

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Scientific Discovery

SPS aspires to drive drug discovery and therapeutic innovation in China's nascent pharmaceutical industry, by strategically positioning its research priorities on three key frontiers of pharmaceutical sciences, namely, fundamental biology, enabling pharmaceutical technologies, and disease understanding and targeting. Below are selected publications by SPS faculty members in 2016. If you wish to learn more about SPS's latest scientific discoveries, please refer to the school website (www.sps.tsinghua.edu.cn) for more information.

ZU Liansuo's research group discovered a method to create completely synthetic molecule of Calophyline A, a natural, nitrogen based chemical compound that is often found in drugs. They published "Total Syntheses of Calophline A" in Angewandte Chemie.

The paper reports the total synthesis of calophyline A, an indoline natural product possessing distinct ring connectivity which has not been synthesized previously. The synthetic route features several key transformations, including an aza-pinacol rearrangement to construct the nitrogen-containing

bridged [3.2.2] bicycle, a Heck cyclization to assemble the fused 6/5/6/5 ring system, and a challenging late-stage aldol reaction to generate both a neopentyl quaternary stereogenic center and an oxygen-containing bridged [3.2.1] bicycle.

1 ZU Liansuo lab publishes "Total Synthesis of Calophyline A" in Angew. Chem. Int. Ed.

WANG Jian lab publishes "Enantioselective Intermolecular Enamide-Aldehyde Cross-Coupling Catalyzed by Chiral N-Heterocyclic Carbenes" in J. Am. Chem. Soc.

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TANG Yefeng and LIU Gang's research g roup success fu l l y syn thes ized Periconiasins A through E. Periconsians are a fungal metabolite. They can stimulate, structure or inhibit enzymes and can also have catalytic activity on their own. Their work has been publ ished as "Total Synthesis of Periconiasins A-E" in Angewandte Chemie.

The paper states that the first and collective total syntheses of periconiasins A-E, a group of naturally occurring cytochalasans, were achieved by a series of rationally designed or bioinspired transformations. Salient features of the syntheses include a tandem aldol condensation/Grob fragmentation to assemble the linear polyketide-amino acid hybrid precursor,

a Diels-Alder macrocylization to construct the 9/6/5 tricyclic core of periconiasins A-C, and a transannular carbonyl-ene reaction to forge the polycycl ic framework of periconiasins D and E.

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XIAO Bailong's research group discovered how mysterious mechanosensitive channels, a family of Piezo proteins, respond to mechanical force and, consequently, conduct ions for biological functions.

In a paper published online in Neuron on February 25th, 2016, the findings of Xiao's laboratory "demonstrate that Piezo1 proteins consist of distinct and separate modules responsible for ion conduction, mechanical force sensing and transduction to coordinately fulfill their function as sophisticated mechanosensitive channels."

In terms of applications, his group's studies "help us understand the specialized force sensors such as Piezo1 ion channels that play critical roles in vascular development and blood cell function, which might enable us to design novel therapeutics in the future to treat diseases caused by abnormal functions of these mechanotransducers."

3 XIAO Bailong lab publishes "Ion Permeation and Mechanotransduction Mechanisms of Mechanosensitive Piezo Channels" in Neuron

TANG Yefeng and LIU Gang lab publishes "Total Syntheses of Periconiasins A-E" in Angew. Chem. Int. Ed.

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LIAO Xuebin 's research group successfu l ly methylated Aryl Halides with Durated Methyl Iodide. His work is published as "Nickel-Catalyzed Methylation of Aryl Halides with Deuterated Methyl Iodide" in Angewandte Chemie.

In this paper, a nickel-catalyzed methylation of aryl halides with cheap and readily available CH3I or CD3I is described. The reaction is applicable to a wide range of substrates and allows installation of a CD3 group under mild reaction conditions without deuterium scrambling to other carbon atoms. Initial

mechanistic studies on the stoichiometric and catalytic reactions of the isolated [(dppp)Ni(C6H4-4-CO2Et)Br] [dppp=1,3-bis(diphenylphosphanyl)propane] suggest that a Ni0 / NiII catalytic cycle is favored.

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CHEN Ligong's research group discovered and characterized new hGLUT1 from homology modeling and virtual screening. His paper "Inhibitor Discovery for the Human GLUT1 from Homology Modeling and Virtual Screening" was published in ACS Chemical Biology.

The human Glucose Transporter 1 (hGLUT1 or SLC2A1) is a facilitative membrane transporter found in the liver, intestines, kidney, and brain, where it transports sugars such as d-glucose and d-galactose. Genetic variations in hGLUT1 are associated with a broad range of diseases and metabolic disorders. For example, hGLUT1 is upregulated in various cancer types (e.g., breast carcinoma) to support the increased anaerobic glycolysis and the Warburg effect. Thus, hGLUT1 is an emerging therapeutic target, which also transports commonly used cancer biomarkers (e.g., 18F-DG).

Chen's lab uses computational prediction followed by experimental testing, to characterize hGLUT1. The lab constructs homology models of hGLUT1 in a partially occluded outward open ("occluded") conformation based on the X-ray structure of the E. coli xylose transporter, XylE. Comparison of the

5 CHEN Ligong lab publishes “Inhibitor Discovery for the Human GLUT1 from Homology Modeling and Virtual Screening” in ACS Chemical Biology

LIAO Xuebin lab publishes “Nickel-Catalyzed Methylation of Aryl Halides with Deuterated Methyl Iodide” in Angew. Chem. Int. Ed.

binding site of the occluded models to experimentally determined hGLUT structures revealed a hydrophobic pocket adjacent to the sugar-binding site, which was tested experimentally via site-directed mutagenesis. Virtual screening of various libraries of purchasable compounds against the occluded models, followed by experimental testing with cellular assays revealed seven previously unknown hGLUT1 ligands with IC50 values ranging from 0.45 μM to 59 μM. These ligands represent three unique chemotypes that are chemically different from any other known hGLUT1 ligands. The newly characterized hydrophobic pocket can potentially be utilized by the new ligands for increased affinity. Furthermore, the previously unknown hGLUT1 ligands can serve as chemical tools to further characterize hGLUT1 function or lead molecules for future drug development.

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LIAO Xuebin's research group discovered a method to synthesize an organic compound, N-hydroxy Oxindoles, without Transition Metals. Synthesizing complex compounds without the assistance of transition metals as catalysts can significantly reduce the cost of drugs. His work, titled "Transition-Metal-Free Synthesis of N-hydroxy Oxindoles by an Aza-Nazarov-Type Reaction Involving Azaoxyallyl Cations" was published in Angewandte Chemie.

TAN Xu's research group, in collaboration with YANG Yong and LIN Zhimiao of Peking University First Hospital discovered a link between a mutation in a gene called KLHL24 and epidermolysis bullosa (EB), a skin disorder that causes extremely fragile skin. Their work, titled "Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility" was published in Nature Genetics.

In this paper, a novel transition-metal-free method to construct N-hydroxy oxindoles by an aza-Nazarov-type reaction involving azaoxyallyl cation intermediates is described. A variety of functional groups were tolerated under the weak basic reaction conditions

This research shows that dominant mutations of KLHL24, encoding a cullin 3–RBX1 ubiquitin ligase substrate receptor, cause EB. They have identified start-codon mutations in the KLHL24 gene in five patients with EB. These mutations lead to truncated KLHL24 protein lacking the initial 28 amino acids (KLHL24-ΔN28). KLHL24-ΔN28 is more stable than its wild-type counterpart owing to abolished autoubiquitination. They have further identified keratin 14 (KRT14) as a KLHL24 substrate and found that KLHL24-ΔN28 induces excessive ubiquitination and degradation of KRT14. Using a knock-in mouse model, they have confirmed that the Klhl24 mutations lead to stabilized Klhl24-ΔN28 and cause Krt14 degradation. Their findings identify a new disease-causing mechanism due to dysregulation of autoubiquitination and open new avenues for the treatment of related disorders.

and at room temperature. A one-pot process was also developed to make the reaction even more practical. This method provides alternative access to oxindoles and their biologically active derivatives.

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LIAO Xuebin lab publishes "Transition-Metal-Free Synthesis of N-hydroxy Oxindoles by an Aza-Nazarov-Type Reaction Involving Azaoxyallyl Cations" in Angew. Chem. Int. Ed.

TAN Xu lab publishes "Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility" in Nature Genetics

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Recently, Dr. HE Wei reached a significant technology transfer agreement with Beijing Jialin Pharmaceutical Co., Ltd. under favorable terms. This "BRM Inhibition Based New Cancer Drug Development Technology" will be further developed at the company for new drug discovery.

Dr. He joined the faculty team at Tsinghua University in January 2011. His main research interests lie in the (nanostructure) metal catalysis and synthesis of drug molecules. Currently, he also serves as the Associate Editor for RSC Advances.

Translational research is one of SPS's key priorities and an essential pathway to realizing its long-term mission of using science and technology to improve human hea l th . SPS has deve loped several advanced platforms in drug discovery, screening and evaluation, providing effective and efficient tools to catalyze the translation of scientific discoveries into clinical applications.

Translational Research

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the pharmaceutical companies, universities, research institutions and hospitals of China and Japan.

The Forum, which will be hosted on an annual basis, is sponsored by Tsinghua Health Science Foundation (THSF) and co-organized by the School of Pharmaceutical Sciences of Tsinghua University. THSF was founded by Takeda Pharmaceutical, EPS Group and Tsinghua University Education Foundation.

Beijing, China, November 11th, 2016 - The inaugural China-Japan "Tsing Yi" Forum was held at Tsinghua University, which gathered more than 100 experts, scholars and government authorities of the pharmaceutical industry from both China and Japan to reflect on "Accelerating the Internationalization of Traditional Chinese Medicine."

The Forum resonates with the "One Belt and One Road Initiative" of the Chinese government. It also aims to promote collaboration and exchange between

Conference and Forum

The inaugural China-Japan "Tsing Yi" Forum successfully held

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SPS strives to create an open and dynamic environment to encourage deep collaborations across various disciplines and sectors. We actively seek partnerships and sponsorships in the education, talent development, research, translational science and technology transfer spaces. Together with our partners, we are building a global ecosystem for biomedical research that can sustainably enable pharmaceutical breakthroughs and enhance the quality of life.

To date, we have already established partnerships with the Bill & Melinda Gates Foundation, Johnson & Johnson, Bristol-Meyers Squibb Company, Bayer, Roche, and Beijing Unisplendour Pharmaceutical etc.

Contact Us

With the generous support of SPS's advocates and through effective collaboration with SPS's partners we will be able to engage in more impactful educational and research activities to tackle the most pressing disease challenges.

If you are thinking about partnering with SPS or wishing to learn more about how to work with SPS, we welcome and value your inquiry sent to the Development Office at tsps_d@tsinghua.edu.cn.

Collaboration and

Development

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School of Pharmaceutical Sciences Medical Science BuildingTsinghua University, Beijing 100084Tel: (8610) 6277 1285www.sps.tsinghua.edu.cnEdited and produced by the Development Office of SPS