Sugimoto Aoi, Koike Tatsuki, Kuboki Yuya, Komaba Sumika, Kosono Shuhei, Aswathy Maniyamma, Anzai Itsuki, Watanabe Tokiko, Toshima Kazunobu, Takahashi Daisuke
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan.
Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Angew Chem Int Ed Engl. 2025 Feb 3;64(6):e202411760. doi: 10.1002/anie.202411760. Epub 2024 Nov 9.
Heparan sulfate (HS) is ubiquitous on cell surfaces and is used as a receptor by many viruses including SARS-CoV-2. However, increased activity of the inflammatory enzyme heparanase (HPSE), which hydrolyses HS, in patients with COVID-19 not only increases the severity of symptoms but also may facilitate the spread of the virus by degrading HS on the cell surface. Therefore, synthetic HPSE blockades, which can bind to SARS-CoV-2 spike protein (SARS-CoV-2-S) and inhibit viral entry, have attracted much attention. This study investigated the development of a new dual-targeting antiviral agent against HPSE and SARS-CoV-2-S using fucoidan as a structural motif. It was found that all-sulfated fucoidan derivative 10, which exhibited the highest binding affinity to SARS-CoV-2-S among 13 derivatives, also showed the highest inhibitory activity against HPSE. Based on this, a newly designed and synthesized fucoidan analogue 16, in which the octyl group of 10 was changed to a cholestanyl group, was found to show approximately 3 times higher activity than 10 but did not inhibit factor Xa associated with undesired anticoagulant effects. The binding affinity of 16 to SARS-CoV-2-S was significantly increased approximately 400-fold over that of 10. The binding of 16 to SARS-CoV-2-S inhibited the binding between SARS-CoV-2-S and heparin and between SARS-CoV-2-S and ACE2. Furthermore, 16 effectively inhibited infection by the SARS-CoV-2 Wuhan strain and two Omicron subvariants.
硫酸乙酰肝素（HS）广泛存在于细胞表面，被包括严重急性呼吸综合征冠状病毒2（SARS-CoV-2）在内的许多病毒用作受体。然而，在2019冠状病毒病（COVID-19）患者中，水解HS的炎性酶乙酰肝素酶（HPSE）活性增加，不仅会加重症状的严重程度，还可能通过降解细胞表面的HS促进病毒传播。因此，能够与SARS-CoV-2刺突蛋白（SARS-CoV-2-S）结合并抑制病毒进入的合成HPSE阻滞剂备受关注。本研究以岩藻依聚糖为结构基序，研究了一种新型的针对HPSE和SARS-CoV-2-S的双靶点抗病毒药物的开发。研究发现，在13种衍生物中，对SARS-CoV-2-S表现出最高结合亲和力的全硫酸化岩藻依聚糖衍生物10，对HPSE也表现出最高的抑制活性。基于此，新设计并合成的岩藻依聚糖类似物16，其10的辛基被改为胆甾烷基，活性比10高约3倍，但不抑制与不良抗凝作用相关的因子Xa。16与SARS-CoV-2-S的结合亲和力比10显著提高了约400倍。16与SARS-CoV-2-S的结合抑制了SARS-CoV-2-S与肝素以及SARS-CoV-2-S与血管紧张素转换酶2（ACE2）之间的结合。此外，16有效抑制了SARS-CoV-2武汉株和两种奥密克戎亚变体的感染。
