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                        CCNU Made Great Progress on Targeted Covalent Inhibition

                        Revision:Hu Qiaoqiao;Xiao YaoDate:2020/05/24

                        Recently, Prof. Jian Wan from the College of Chemistry of CCNU made great progress on the research of Fructose-1, 6-bisphosphatase (FBPase) in Pharmaceutical Chemistry and pharmacology, cooperated with Prof. Jian Li’s research team from the School of Pharmacy of East China University of Science and Technology (ECUST). The research results were published on Journal of Medicinal Chemistry. The first author of the paper is 2016 Ph.D. candidate Yunyuan Huang. Associate Professor Yanliang Ren and Prof. Jian Wan from CCNU and Prof. Jian Li are co-corresponding authors. The first institute is Laboratory of Pesticides and Chemistry Key Laboratory of Ministry of Education in CCNU.

                        FBPase is considered as a new potential target associated with cancer and type 2diabetes. Therefore, the discovery of the drugs targeting to FBPase is critical to the designment and development of new type of hypoglycemic drug and anti-cancer drug. Prof. Jian Wan found a new cysteine C128 covalent allosteric site (Eur. J. Med. Chem., 184, 2019, 111749) and got a series of more potent covalent inhibitors through the de novo drug design method of covalent drug developed by the research group (J. Chem. Theory Comput., 15, 2019,4264; J. Chem. Inf. Model., 2020, DOI:10.1021/acs.jcim.9b01197). However, the allosteric mechanism of C128 covalent site is still unclear.

                        The team of Prof. Jian Wan and Prof. Jian Li cooperatively found that the disulfiram herein could potently inhibit FBPase by covalently binding to a new C128 allosteric site distinct from the original C128 site in APO FBPase and show certain hypoglycemic activity in mice. Notably, they were the first to resolve the crystallographic structure of disulfiram derivatives complex with FBPase, and identify the mechanism of C128 covalent allosteric inhibition using diffraction technique of protein crystal. They also found that the addition of inhibitor and FBPase can result in the movement of residue C128 and the change of hydrogen-bond networks nearby the C128 site, finally generate a novel C128 binding pocket. This research not only identifies a new covalent allosteric site of FBPase, but also establishes a structual foundation and provides a promising way for the design of covalent allosteric drugs.

                        Journal of Medicinal Chemistry is a top international authoritative journal in the field of pharmaceutical chemistry affiliated to American Chemical Society. It is the first time that CCNU has published research results as the first institute in this journal, marking that CCNU has advance to a new level in pharmaceutical chemistry.

                        The research is supported by National Natural Science Foundation (21877046, 21873035) and the self-determined research funds of CCNU from the colleges’ basic research and operation of MOE (CCNU19TS011, CCNU18TS010, 2018YBZZ019). BL19U beamline of the NCPSS at Shanghai Synchrotron Radiation Facility (SSRF) and National Center for Protein Science Shanghai provide support for data collection.

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