CPU Frontier | Latest Research Progress Episode 2

Release date:2018-05-23  Release:主页英文版

CPU Frontier | Latest Research Progress Episode 2


This column mainly reports the latest scientific research progress related to CPU. It is hoped that it will be convenient for the majority of CPUers to learn more about pharmaceutical research. The following articles are sorted by discipline.


Original Chinese version by WeChat official account “CPUinsight”, NewMedia Center, China Pharmaceutical University, Edited by Wang Yongming

Translated by Liu Qi, Office of International Exchange & Cooperation, China Pharmaceutical University




PNAS | Yu Ye, Motoyuki Hattori and Wang Rui discovered the druggable negative allosteric site of P2X3 receptors


Recently, the United States National Academy of Sciences (PNAS, influence factor 9.423) reported druggable negative allosteric site of P2X3 receptors--the latest achievement by Prof. Yu Ye, Motoyuki Hattori and Wang Rui. Their research work combined structural biology, computational biology, and biochemistry, and provided a new starting point for related drug development.

Professor YU Ye, recently employed by China Pharmaceutical University, was the leader of the research group of "Membrane Biophysics and Chemical Biology" at School of Medicine, Shanghai Jiao Tong University from March 2011 to March 2018. He has won “Young scholar of the Yangtze River Award” of the Ministry of Education and “Outstanding Youth Fund” of China.

P2X receptors are extracellular ATP-gated ion channels and play an important role in various physiological and pathological processes. Drug development targeting P2X receptors has entered clinical trials in the treatment of arthritis, pain and other diseases. At present, the academia knows little about the mechanism of allosteric regulation of P2X, which has caused great obstacles to related drug development. In their research work, Yu et al identified the key amino acid residues and allosteric regulation of ligand-receptor interactions by using P2X3 specific allosteric inhibitors AF353 and AF219, together with site-directed mutagenesis techniques, in response to the structural features of P2X3 receptors. It was found that this allosteric site of P2X3 is completely different from the previously reported P2X7 allosteric site, which has important reference value for drug development targeting P2X3 receptors.


http://rcb.cpu.edu.cn/6b/9e/c1057a93086/page.htm Introduction to Prof. YU Ye’s research work and publications


Pharmacol Ther | Professor Zhang Luyong's team published a review article on non-alcoholic fatty liver disease

Recently, Pharmacology & Therapeutics (IF 11.127) published a review article Bile Acid Regulation: A Novel Therapeutic Strategy in Non-Alcoholic Fatty Liver Disease. The first author of this article is doctoral candidate Yu Qinwei. Prof. Zhang Luyong and Jiang Zhenzhou are co-corresponding authors of this article. Prof. Zhang Luyong is the director of New Drug Screening Center of China Pharmaceutical University and also the vice president of Guangdong Pharmaceutical University.

Non-alcoholic fatty liver disease (NAFLD) has become a common liver disease and has attracted increasing attention. The article first introduced the concept of NAFLD in detail, and introduced the pathological features of NAFLD from oxidative stress and intestinal flora. Subsequently, the author also conducted a detailed analysis and review of the relationship between NAFLD and bile acid metabolism. Afterwards, the author further introduced the effects of bile acid metabolism on lipid metabolism, immune regulation, and intestinal flora, and proposed strategies and methods for preventing and treating NAFLD from different perspectives. In addition, the author also introduced drugs for the treatment of disorders of bile acid metabolism, analyzed and summarized the difficulties encountered in drug development, and looked forward to the future research.

This article reviews the pathological research, clinical treatment, drug application and research and development of NAFLD from the perspective of bile acid metabolism. A comprehensive and in-depth summary of recent studies on the regulation of bile acid metabolism and the field of NAFLD therapy has been completed, and the ideas for related fields have been clarified.


J Med Chem | Prof. Hao Haiping and Prof. Jiang Yi cooperatively published review article on NQO1

Recently, Journal of Medicinal Chemistry, a key journal in the field of medicinal chemistry (IF 6.259), published a review article NAD(P)H: Quinone Oxidoreductase 1 (NQO1). ) as a Therapeutic and Diagnostic Target in Cancer. Prof. Hao Haiping and Prof. Jiang Wei of CPU School of Pharmacy are the co-corresponding authors of this article.  Zhang Kuojun, a doctoral student of Prof. Jiang Wei's research group, is the first author of this article.

NQO1 is a two-electron reductase in cells, which is over-expressed in a variety of tumor cells and closely related to the occurrence and development of tumors. NQO1 can bioactivate its substrate, reducing its structure to hydroquinone. Representative substrates include β-lapachone and tanshinone IIA. This article summarized the NQO1 target and related research from the aspects of NQO1 discovery, the biological role of NQO1, and the development of drugs and fluorescent probes with NQO1 as the target.

Although there is currently no drug with NQO1 as a target, NQO1 can bioactivate NQO1 substrate, which provides a basis for the design and development of relevant targeted prodrugs. This strategy is expected to be applied to the development of anti-tumor drugs and diagnostic reagents. in.



J Med Chem | Sun Liping, Xie Hua, and Zhang Wei Collaborate on Novel BTK Inhibitors

Recently, Journal of Medicinal Chemistry (IF 6.259), the authoritative journal of the field of medicinal chemistry, published the research article Discovery of 4,7-Diamino-5. -(4-phenoxyphenyl)-6-methylene-pyrimido[5,4-b] pyrrolizines as Novel Bruton's Tyrosine Kinase (BTK) Inhibitors by Professor Sun Liping of China Pharmaceutical University, and Researchers Xie Hua and Zhang Hao of Shanghai Institute of Materia Medica.

BTK as a non-receptor tyrosine kinase participates in various biological processes of B cell receptor signaling pathway. The first generation of BTK inhibitor Ibrutinib was approved by the FDA in 2013 for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia. Prof. Sun Liping of China Pharmaceutical University, researcher of Xie Hua of the Shanghai Institute of Drugs and researcher of Zhang Hao cooperated with each other. With ibrutinib as a template molecule, the bicyclic ring structure of ibrutinib was changed to a tricyclic structure. Two new types of BTK inhibitors (Fig. 1). The compound was then optimized based on the covalent binding site and the pharmacokinetic properties of BTK Cys481 to give compound 7S. Compared to ibrutinib, compound 7S has stronger BTK inhibitory activity, and in vivo results also show that compound 7S is superior to ibrutinib.

This work is based on the structural characteristics of the IBR inhibitor, ibrutinib. The tricyclic mother nucleus structure was subtly constructed and a more active new type of BTK inhibitor was obtained. It is worth further research and exploration.


Theranostics | Yin Lifang and He Wei team report intracellular MMPs efficiently inhibits tumor metastasis


Matrix metalloproteinases (MMPs) are the most important class of enzymes in the extracellular matrix. They can degrade the extracellular matrix and facilitate the tumor metastasis. Studies have shown that inhibition of tumor microenvironment (TME) MMPs can significantly inhibit tumor metastasis. The coordinated delivery of the two drugs can effectively treat the tumor, but the target of chemotherapeutic drugs is generally located intracellular, and MMPs are present in the TME, and it is more difficult to deliver drugs to these two sites at the same time.

Prof. Yin Lifang and Associate Professor He Wei of China Pharmaceutical University published a paper in the journal Theranostics (IF: 8.766) in the 1st edition of the Journal of Biomedicine. It reported on a protein as a delivery vehicle and delivered antitumor prodrugs and matrix metalloproteinase inhibitors simultaneously. Anti-metastasis and pro-apoptosis can be achieved by inhibiting intracellular MMPs, avoiding cumbersome design of drug delivery to two different sites, and the preparation of the carrier is simple and effective.

In this study, researchers first used casein (β-CN) to form a protein complex with the matrix metalloproteinase inhibitor MATT, and then assembled with the anti-tumor prodrug hyaluronic acid-paclitaxel (HA-PTX) to form nanoparticles. The formation of nanocarriers and the interaction of HA and CD44 receptors can significantly increase the uptake of drugs by tumor cells and achieve efficient drug delivery. And only the protein as material guarantees the safety of the carrier. β-CN can deliver both drugs into the cell at the same time, realizing the synergistic treatment of the two drugs on the tumor, which can obviously induce cell apoptosis and inhibit tumor metastasis. The research results show that inhibition of intracellular MMPs can also achieve anti-metastasis and anti-angiogenesis effects, providing important ideas for the inhibition of tumor metastasis and the design of new drug delivery systems.

Prof. Yin Lifang and Associate Professor He Wei of China Pharmaceutical University were the two co-corresponding authors of the article. Lu Yaqi, member of the research group, was the first author of the article. The study was funded by the National Natural Science Foundation of China (Project Nos. 81673377, 81473152, 81402869) and the Natural Science Foundation of Jiangsu Province (Project No. BK20140671).


Mol Cell Proteomics | Hao Haiping Team Reports New Mechanism of Butyric Acid Inhibition of Colorectal Cancer

Recently, Molecular & Cellular Proteomics (IF 6.540), the authoritative journal in the field of proteomics, published the latest research results of Professor Hao Haiping’s team – Butyrate Suppresses the Proliferation of Colorectal Cancer Cells via Targeting Pyruvate Kinase M2 and Metabolic Reprogramming. Ph.D. candidates Li Qingran and associate researcher Cao Lijuan are the co-first authors of this article. Professors Hao Haiping and Ye Hui are co-corresponding authors of this article.

In recent years, the team has achieved a number of important achievements in the study of metabolic regulation of endogenous small molecules such as bile acids and tryptophan. In this work, researchers used metabolomics and proteomics to conduct in-depth research and exploration around the short-chain fatty acid butyric acid, revealing that butyric acid inhibits the proliferation of colorectal cancer cells. Based on the metabolomics platform built by the research group, it has been found that under the action of butyric acid, the pyruvate accumulation in HCT-116 cells was significantly greater and its upstream intermediates were reduced. Using DARTS-based proteomics technology, pyruvate kinase PKM2 was found to be a direct target of butyrate. Butyric acid activates PKM2 by promoting the dephosphorylation and tetramerization of PKM2, which leads to reprogramming of the colorectal cancer cells, inhibits the Warburg effect, and inhibits tumor cell proliferation.

This study revealed the specific molecular mechanisms of antitumor effects of butyric acid. The combined strategy of metabonomics and proteomics reveals the target of butyrate, which has important guiding significance for future target discovery and mechanism research of endogenous small molecules.