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
  • 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.
Products