Abdulsalam Hawau, Li Jiayi, Loka Ravi S, Sletten Eric T, Nguyen Hien M
Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States.
Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Muehlenberg 1, 14476 Potsdam, Germany.
ACS Med Chem Lett. 2023 Sep 29;14(10):1411-1418. doi: 10.1021/acsmedchemlett.3c00319. eCollection 2023 Oct 12.
Heparan sulfate-mimicking glycopolymers, composed of glucosamine (GlcN)-glucuronic acid (GlcA) repeating units, bind to the receptor-binding subunit (S1) and spike glycoprotein (S) domains of the SARS-CoV-2 spike protein in a length- and sulfation pattern-dependent fashion. A glycopolymer composed of 12 repeating GlcNS6S-GlcA units exhibits a much higher affinity to the S1 protein (IC = 13 ± 1.1 nM) compared with the receptor-binding domain (RBD). This glycopolymer does not interfere in angiotensin-converting enzyme 2 binding of the RBD. Although this compound binds strongly to the S1/membrane-fusion subunit (S2) junction ( = 29.7 ± 4.18 nM), it does not shield the S1/S2 site from cleavage by furin-a behavior contrary to natural heparin. This glycopolymer lacks iduronic acid, which accounts for 70% of heparin. Further, this compound, unlike natural heparin, is well defined in both sulfation pattern and length, which results in fewer off-target interactions with heparin-binding proteins. The results highlight the potential of using polymeric heparan sulfate (HS) mimetics for the therapeutic agent development.
由葡糖胺（GlcN）-葡糖醛酸（GlcA）重复单元组成的硫酸乙酰肝素模拟糖聚合物，以长度和硫酸化模式依赖的方式与严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突蛋白的受体结合亚基（S1）和刺突糖蛋白（S）结构域结合。与受体结合结构域（RBD）相比，由12个重复的GlcNS6S-GlcA单元组成的糖聚合物对S1蛋白表现出更高的亲和力（IC = 13 ± 1.1 nM）。这种糖聚合物不干扰RBD与血管紧张素转换酶2的结合。尽管该化合物与S1/膜融合亚基（S2）连接处紧密结合（ = 29.7 ± 4.18 nM），但它不能保护S1/S2位点不被弗林蛋白酶切割，这一行为与天然肝素相反。这种糖聚合物缺乏艾杜糖醛酸，而艾杜糖醛酸占肝素的70%。此外，与天然肝素不同，该化合物在硫酸化模式和长度方面都有明确的定义，这导致与肝素结合蛋白的脱靶相互作用较少。这些结果突出了使用聚合硫酸乙酰肝素（HS）模拟物开发治疗剂的潜力。
