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

Liping Liao; Wenzhen Dang; Tingting Lin; Jinghua Yu; Tonghai Liu; Wen Li; Senhao Xiao; Lei Feng; Jing Huang; Rong Fu; Jiacheng Li; Liping Liu; Mingchen Wang; Hongru Tao; Hualiang Jiang; Kaixian Chen; Xingxing Diao; Bing Zhou; Xiaoyan Shen; Cheng Luo

doi:10.1016/j.apsb.2022.05.012

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. Epub 2022 May 14.

Authors

Liping Liao^{1

2}, Wenzhen Dang^{3

1}, Tingting Lin^{1

2}, Jinghua Yu¹, Tonghai Liu^{1

2}, Wen Li¹, Senhao Xiao^{1

2}, Lei Feng^{1

2}, Jing Huang^{1

2}, Rong Fu¹, Jiacheng Li^{1

2}, Liping Liu^{1

2}, Mingchen Wang^{1

2}, Hongru Tao¹, Hualiang Jiang^{1

2}, Kaixian Chen^{1

2}, Xingxing Diao¹, Bing Zhou^{1

4}, Xiaoyan Shen³, 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.

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.