2. Academic Validation
  3. Development of disulfide-derived fructose-1,6-bisphosphatase (FBPase) covalent inhibitors for the treatment of type 2 diabetes

Development of disulfide-derived fructose-1,6-bisphosphatase (FBPase) covalent inhibitors for the treatment of type 2 diabetes

  • Eur J Med Chem. 2020 Oct 1;203:112500. doi: 10.1016/j.ejmech.2020.112500.
Yi-Xiang Xu 1,  Yun-Yuan Huang 2,  Rong-Rong Song 3,  Yan-Liang Ren 3,  Xin Chen 1,  Chao Zhang 1,  Fei Mao 1,  Xiao-Kang Li 1,  Jin Zhu 1,  Shuai-Shuai Ni 4,  Jian Wan 5,  Jian Li 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China.
  • 2 State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China; Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, 430079, China.
  • 3 Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, 430079, China.
  • 4 Cancer Institute, Longhua Hospital Shanghai University of Traditional Chinese Medicine, 725 South Wan Ping Road, Shanghai, 200032, China. Electronic address: [email protected].
  • 5 Key Laboratory of Pesticide & Chemical Biology (CCNU), Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, 430079, China. Electronic address: [email protected].
  • 6 State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China. Electronic address: [email protected].
PMID: 32711108 DOI: 10.1016/j.ejmech.2020.112500
Abstract

Fructose-1,6-bisphosphatase (FBPase), as a key rate-limiting Enzyme in the gluconeogenesis (GNG) pathway, represents a practical therapeutic strategy for type 2 diabetes (T2D). Our previous work first identified cysteine residue 128 (C128) was an important allosteric site in the structure of FBPase, while pharmacologically targeting C128 attenuated the catalytic ability of FBPase. Herein, ten approved cysteine covalent drugs were selected for exploring FBPase inhibitory activities, and the alcohol deterrent disulfiram displayed superior inhibitory efficacy among those drugs. Based on the structure of lead compound disulfiram, 58 disulfide-derived compounds were designed and synthesized for investigating FBPase inhibitory activities. Optimal compound 3a exhibited significant FBPase inhibition and glucose-lowering efficacy in vitro and in vivo. Furthermore, 3a covalently modified the C128 site, and then regulated the N125-S124-S123 allosteric pathway of FBPase in mechanism. In summary, 3a has the potential to be a novel FBPase Inhibitor for T2D therapy.

Keywords

Covalent inhibitors; Diabetes; Disulfiram; Drug repurposing; FBPase.

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