Novel bivalent inhibitors with sub-nanomolar affinities towards human glyoxalase I

Yankui Sang; Qing Shi; Mingguang Mo; Caixia Ni; Zonghe Li; Bichong Liu; Qishan Deng; Donald J Creighton; Zhe-Bin Zheng

doi:10.1016/j.bmcl.2015.08.055

Novel bivalent inhibitors with sub-nanomolar affinities towards human glyoxalase I

Bioorg Med Chem Lett. 2015 Nov 1;25(21):4724-4727. doi: 10.1016/j.bmcl.2015.08.055. Epub 2015 Aug 20.

Authors

Yankui Sang¹, Qing Shi¹, Mingguang Mo¹, Caixia Ni¹, Zonghe Li¹, Bichong Liu¹, Qishan Deng¹, Donald J Creighton², Zhe-Bin Zheng³

Affiliations

¹ Department of Antibiotic Research & Re-evaluation, Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Huaguan Road 168, Chengdu City, Sichuan Province 610052, PR China.
² Department of Chemistry & Biochemistry, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA.
³ Department of Antibiotic Research & Re-evaluation, Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Huaguan Road 168, Chengdu City, Sichuan Province 610052, PR China. Electronic address: [email protected].

PMID: 26320622
DOI: 10.1016/j.bmcl.2015.08.055

Abstract

The zinc metalloenzyme glyoxalase I (GlxI) catalyzes the glutathione-dependent inactivation of cytotoxic methylglyoxal. Two competitive bivalent GlxI inhibitors, polyBHG2-62 (Ki=1.0 nM) and polyBHG2-54 (Ki=0.3 nM), were synthesized based on the transition-state analog S-(N-bromophenyl-N-hydroxycarbamoyl) glutathione (BHG). The most effective inhibitor, polyBHG2-54, is the first subnanomolar inhibitor of GlxI, and is over 50-fold more potent than BHG itself.

Keywords: Bivalent inhibitor; Glyoxalase I; Linker; Methylglyoxal.

Publication types

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

MeSH terms

Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
Humans
Lactoylglutathione Lyase / antagonists & inhibitors*
Lactoylglutathione Lyase / metabolism*
Molecular Structure
Structure-Activity Relationship

Substances

Enzyme Inhibitors
GLO1 protein, human
Lactoylglutathione Lyase