Discovery of a Bioactive Inhibitor with a New Scaffold for Cystathionine γ-Lyase

Youtian Hu; Lu Wang; Xu Han; Yueyang Zhou; Tonghui Zhang; Li Wang; Ting Hong; Wei Zhang; Xun-Xiang Guo; Jielin Sun; Yingxin Qi; Jing Yu; Hong Liu; Fang Wu

doi:10.1021/acs.jmedchem.8b01720

Discovery of a Bioactive Inhibitor with a New Scaffold for Cystathionine γ-Lyase

J Med Chem. 2019 Feb 14;62(3):1677-1683. doi: 10.1021/acs.jmedchem.8b01720. Epub 2018 Dec 31.

Authors

Youtian Hu¹, Lu Wang², Xu Han³, Yueyang Zhou¹, Tonghui Zhang¹, Li Wang¹, Ting Hong^{1

4}, Wei Zhang⁵, Xun-Xiang Guo¹, Jielin Sun¹, Yingxin Qi², Jing Yu⁵, Hong Liu³, Fang Wu¹

Affiliations

¹ Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine , Shanghai Jiao Tong University , Shanghai 200240 , China.
² Institute of Mechanobiology and Medical Engineering, School of Life Sciences and Biotechnology , Shanghai Jiao Tong University , Shanghai 200240 , China.
³ State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China.
⁴ Science and Technology College , Jiangxi University of Traditional Chinese Medicine , Nanchang 330004 , China.
⁵ State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences & Biotechnology , Shanghai Jiao Tong University , Shanghai 200240 , China.

PMID: 30562026
DOI: 10.1021/acs.jmedchem.8b01720

Abstract

We identify three submicromolar inhibitors with new chemical scaffolds for cystathionine γ-lyase (CSE) by a tandem-well-based high-throughput assay. NSC4056, the most potent inhibitor with an IC₅₀ of 0.6 μM, which is also known as aurintricarboxylic acid, selectively binds to Arg and Tyr residues of CSE active site and preferably inhibits the CSE activity in cells rather than cystathionine β-synthase (CBS), the other H₂S-generating enzyme. Moreover, NSC4056 effectively rescues hypotension in hemorrhagic shock rats.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aurintricarboxylic Acid / chemistry
Aurintricarboxylic Acid / metabolism
Aurintricarboxylic Acid / pharmacology*
Catalytic Domain / drug effects
Cystathionine gamma-Lyase / antagonists & inhibitors*
Cystathionine gamma-Lyase / chemistry
Cystathionine gamma-Lyase / metabolism
Drug Discovery
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
HEK293 Cells
Humans
Male
Mice
Molecular Docking Simulation
Molecular Structure
Nitroquinolines / pharmacology
Protein Binding
RAW 264.7 Cells
Rats, Sprague-Dawley
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Nitroquinolines
Aurintricarboxylic Acid
nitroxoline
Cystathionine gamma-Lyase