Poster Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2024

Novel Approach to Anti-tumor and Anti-SARS-COV-2 Drugs by Modulating Sialylation of N-Glycans (#206)

Wen-Shan Li 1 , Ser John L Perez 2 , Tzu-Ting Chang 3 , Chia-Ling Chen 2 , Shih-Han Wang 4 , Chia-Wei Li 4 , Hsing-Pang Hsieh 5 , Han-Chung Wu 6
  1. Institute of Chemistry, Academia Sinica, Taipei, Taiwan
  2. Sustainable Chemical Science and Technology Program, Taiwan International Graduate Program, Academia Sinica, Taipei , Taiwan
  3. Biomedical Translational Research Center, Academia Sinica, Taipei, Taiwan
  4. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
  5. Institute of Biotech and Pharma Research, National Health Research Institutes, Miaoli County, Taiwan
  6. Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan

Variations in cell surface sialylation are known to play an important role in tumor cell invasion and metastasis. Modifications of sialylation in vivo are mediated by several glycoprotein- and glycolipid-specific sialyltransferases (STs). At present, few selective STs inhibitors with a cell-permeable property have been documented [1]. In addition, observations of sialylated glycans, specifically glycolipids, facilitate viral entry of SARS-CoV-2 are confirmed and validated [2]. Thus, the discovery of anti-SARS-CoV2 agents that can target specific ST isozymes in vivo, is essential for the development of effective chemical therapeutics to prevent viral infection.

To address the scarcity of novel STs inhibitors, we now report the synthesis and biological evaluation of new and novel bishomolithocholic acid derivatives with promising therapeutic potential against breast cancer growth and SARS-CoV-2 infection. Among the series, SPP-037 preferentially inhibited the activity of ST6GAL1 (sialylation of N-glycan) with an IC50 value of 3.6 μM over ST3GAL1 (IC50 > 500 μM; sialylation of O-glycan)). In vitro cell-based assays revealed that SPP-037 suppressed MDA-MB-231 cell migration and HUVEC tube formation. Moreover, administration of SPP-037 to tumor-bearing mice resulted in reduced tumor growth, thereby highlighting its anticancer activity.

Furthermore, we validated that SARS-CoV-2 upregulates ST6GAL1 expression and sialylation using RT-qPCR analysis, immunohistochemistry and immunofluorescence imaging assays. It was found that treatment of A549-hACE2 cells with SPP-037 attenuated cellular sialylation, substantially decreasing SARS-CoV-2 infection. Our results underscore the feasibility of ST6GAL1 inhibition as an ingenious therapeutic intervention to suppress SARS-CoV-2 infectivity.

  1. [1].     Perez, S. J. L. P., Fu, C. W., Li, W. S., "Sialyltransferase Inhibitors for the Treatment of Cancer Metastasis: Current Challenges and Future Perspectives," Molecules, 2021, 26, 5673.
  2. [2].     Nguyen et al. "Sialic acid-containing glycolipids mediate binding and viral entry of SARS-CoV-2," Nat Chem Biol., 2022, 18, 81.