TCM theory-inspired discovery of DNJ-flavonoid conjugates as broad-spectrum anti-SARS-CoV-2 agents by primarily targeting ER-associated glycoprotein folding process

  • Eur J Med Chem. 2025 Jun 5:290:117582. doi: 10.1016/j.ejmech.2025.117582.
Yan-Yun Liu  1 ,  Zheng-Ao Li  1 ,  Yu-Zheng Zhou  2 ,  Sen-Lin Wang  1 ,  Zong-Peng Chen  3 ,  Si-Xu Liu  3 ,  Peng Zhan  4 ,  Ying-Jun Zhou  5 ,  Zan-Xian Xia  6 ,  Xu Deng  7
Affiliations
  • 1. Xiangya School of Pharmaceutical Science, Central South University, Changsha, 410013, Hunan, China.
  • 2. Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China.
  • 3. School of Life Sciences, Central South University, Changsha, 410013, Hunan, China.
  • 4. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Ji'nan, Shandong, 250012, China.
  • 5. Xiangya School of Pharmaceutical Science, Central South University, Changsha, 410013, Hunan, China; Hunan Key laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, 410013, Hunan, China.
  • 6. School of Life Sciences, Central South University, Changsha, 410013, Hunan, China. Electronic address: [email protected].
  • 7. Xiangya School of Pharmaceutical Science, Central South University, Changsha, 410013, Hunan, China; Hunan Key laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, 410013, Hunan, China. Electronic address: [email protected].
PMID: 40168909 DOI: 10.1016/j.ejmech.2025.117582
Abstract

The global COVID-19 pandemic caused by SARS-CoV-2 has underscored the urgent need for the development of new broad-spectrum antivirals to combat its high mutation rate and the emerging variants. Host ER α-glucosidases I/II are promising host-targeted therapeutic targets for the development of broad-spectrum antivirals against viral strains that depend on ERQC for infectivity. Herein, we designed and synthesized a series of TCM theory-inspired DNJ-flavonoid conjugates as novel α-glucosidase inhibitors, which were screened against their in vitro Antiviral activities in non-replicative SARS-CoV-2 pseudovirus (PsV) assay. Remarkably, DNJ-20 not only demonstrated remarkable inhibition activity against α-glucosidase and viral entry process, but also exerted potent and broad-spectrum anti-coronaviral activity against SARS-CoV-2 pseudovirus (PsV), several SARS-CoV-2 variants, as well as HCoV-229E and HCoV-OC43, with EC50 values up to 1.49 μM, which is more potent than the benchmark α-glucosidase inhibitor UV-4 (DNJ-3). Besides, it had no observable cytotoxicity in HeLa-ACE2, HEK-293T and Beas-2B cells. Therefore, TCM theory-inspired DNJ-flavonoid conjugates can be served as promising drug leads for pan-coronavirus therapeutic development to combat current and future coronavirus pandemics.

Keywords
Broad-spectrum antivirals; DNJ-Flavonoid conjugates; ER α-glucosidase inhibitors; SARS-CoV-2; TCM-inspired drug design.
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