國家衛生研究院 NHRI:Item 3990099045/16418
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    题名: Novel approach to anti-tumour and anti-SARS-COV-2 drugs by modulating sialylation of N-glycans
    作者: Li, WS;Perez, SJL;Chang, TT;Chen, CL;Wang, SH;Li, CW;Hsieh, HP;Wu, HC
    贡献者: Institute of Biotechnology and Pharmaceutical Research
    摘要: Variations in cell surface sialylation are known to play an important role in tumour cell invasion and metastasis. Modifications of sialylation in vivo are mediated by several glycoprotein-and glycolipid-specific sialytransferases (STs). At present, few selective STs inhibitors with a cell-permeable property have been documented. In addition. observations of sialylated glycans, specifically glycolipids. facilitate viral entry of SARS-CoV-2 are confirmed and validated. Thus, the discovery of anti-SARS-Co-2 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>500µM; sialyation of O-glycan)). In vitro cell-based assays revealed that SPP-037 suppressed MDA-MB-231cell migration and HUVEC tube formation. Moreover, administration of SPP-037 to tumour-bearing mice resulted in reduced tumour 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 infections. Our results underscore the feasibility of ST6GAL1 inhibition as an ingenious therapeutic intervention to suppress SARS-CoV-2 infectivity.
    日期: 2024-11-07
    關聯: Asia-Pacific Journal of Clinical Oncology. 2024 Nov 07;20:116-117.
    Link to: https://doi.org/10.1111/ajco.14117
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:001352150600144
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