2. Academic Validation
  3. A potent PGK1 antagonist reveals PGK1 regulates the production of IL-1 β and IL-6

A potent PGK1 antagonist reveals PGK1 regulates the production of IL-1 β and IL-6

  • Acta Pharm Sin B. 2022 Nov;12(11):4180-4192. doi: 10.1016/j.apsb.2022.05.012.
Liping Liao 1 2,  Wenzhen Dang 3 1,  Tingting Lin 1 2,  Jinghua Yu 1,  Tonghai Liu 1 2,  Wen Li 1,  Senhao Xiao 1 2,  Lei Feng 1 2,  Jing Huang 1 2,  Rong Fu 1,  Jiacheng Li 1 2,  Liping Liu 1 2,  Mingchen Wang 1 2,  Hongru Tao 1,  Hualiang Jiang 1 2,  Kaixian Chen 1 2,  Xingxing Diao 1,  Bing Zhou 1 4,  Xiaoyan Shen 3,  Cheng Luo 3 1 2 4 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 Department of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 4 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 5 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
PMID: 36386479 DOI: 10.1016/j.apsb.2022.05.012
Abstract

Glycolytic metabolism Enzymes have been implicated in the immunometabolism field through changes in metabolic status. PGK1 is a catalytic enzyme in the glycolytic pathway. Here, we set up a high-throughput screen platform to identify PGK1 inhibitors. DC-PGKI is an ATP-competitive inhibitor of PGK1 with an affinity of K d = 99.08 nmol/L. DC-PGKI stabilizes PGK1 in vitro and in vivo, and suppresses both glycolytic activity and the kinase function of PGK1. In addition, DC-PGKI unveils that PGK1 regulates production of IL-1β and IL-6 in LPS-stimulated macrophages. Mechanistically, inhibition of PGK1 with DC-PGKI results in NRF2 (nuclear factor-erythroid factor 2-related factor 2, NFE2L2) accumulation, then NRF2 translocates to the nucleus and binds to the proximity region of Il-1β and IL-6 genes, and inhibits LPS-induced expression of these genes. DC-PGKI ameliorates colitis in the dextran sulfate sodium (DSS)-induced colitis mouse model. These data support PGK1 as a regulator of macrophages and suggest potential utility of PGK1 inhibitors in the treatment of inflammatory bowel disease.

Keywords

Glycolysis; Inflammation; Macrophages; NRF2; Phosphoglycerate kinase1.

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