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"Tandem-well-based assay tells aurintricarboxylic acid, an old drug, to be a pharmacological inhibitor of H2S production

Recently, Journal of Medicinal Chemistry (IF = 6.253), the American Chemical Society's top journal in the field of medicinal chemistry online published the latest research results of hydrogen sulfide gas producing enzyme inhibitors, this work was accomplished by Wu Fang' research group in Shanghai Center for Systems Biomedicine. The find was also selected by the journal editor as the Supplementary Journal Cover to be highlighted. This work constructed a high-throughput drug screening model for H2S gas production enzyme cystathionine γ-lyase(CSE), found the most efficient CSE activity inhibitor at present, systematically studied the molecular and cellular mechanism and the structural-activity relationship of this inhibitor, and revealed that this inhibitor can treat hemorrhagic shock.

Cystathionine γ-Lyase (CSE) is one of the key enzymes for the synthesis of hydrogen sulfide, a gas signaling molecule, it mainly exists in peripheral tissues and is closely related to hemorrhagic shock, snoring and a variety of immune disorders. Currently, it is a new drug target for the treatment of these diseases. However, the known inhibitor of CSE has low activity and poor selectivity, which prevents its application in scientific research and clinical practice. In this study, the researchers used the previously established high-throughput gas detection method 192-tandem-well-plate(Chem. Commun. 2013; the plate was recently authorized by the Chinese Patent Office: CN104569377A) to carry out the largest high-throughput inhibitor screening for CSE enzyme so far (screening nearly 12,000 compounds), and found three small-molecule selective inhibitors for CSE.

Among them, the half inhibitory concentration (IC50) of "old drug" aurintricarboxylic acid on CSE is 0.6 μM, which is the most effective inhibitor of CSE at present. Furthermore, through a series of biochemical, medicinal chemical, and biophysical research methods, it is revealed that the Arg62, Tyr114, and Arg119 are the key residues for the identification of these inhibitors. The effectiveness and selectivity of aurintricarboxylic acid on macrophage Raw264.7 were confirmed by hydrogen sulfide imaging on cell level, lead acetate method and mutation test, and NSC4056 was found to be effective in recovering blood pressure of hemorrhagic shock animals in rat hemorrhagic shock model.

The article titled "Discovery of a Bioactive Inhibitor with a New Scaffold for Cystathionine γ‑Lyase (DOI: 10.1021/acs.jmedchem.8b01720.)” was published online in December 18, 2018. Shanghai Center for Systems Biomedicine of Shanghai Jiao Tong University was the first corresponding institute, and Dr. Youtian Hu, is the main author. Lu Wang, Ph.D of School of Life Sciences and Biotechnology of Shanghai Jiao Tong University, and Xu Han, Ph.D of Shanghai Institute of Materia Medica of Chinese Academy of Sciences are co-first authors. Prof. Fang Wu, Prof. Hong Liu, and associate Prof. Jing Yu are corresponding authors.

This work has been funded by the National Natural Science Foundation of China and the Special Fund for the Cultivation of Young Teachers in Shanghai Jiao Tong University.

Paper link:

Legend:The proportional and complementary design is not only gems of human civilization but also cornerstones for pharmaceutical research. The cover shows that designing and performing of tandem-well-based high-throughput screening assay could generate new drug leads for H2S-related diseases.

 The grid-shaped model of human body represents that the human body itself has many mysterious codes, such as the golden ratio (see Leonardo Da Vinci's sketch”The vitruvian proportions study”).

Copyright: 2013 Young Scientist Laboratory of Shanghai Jiaotong University       Technical Support: Shanghai Yi-chao Information Technology Co., Ltd.