Froese Jurij, Mandalari Marco, Civera Monica, Elli Stefano, Pagani Isabel, Vicenzi Elisa, Garcia-Monge Itzel, Di Iorio Daniele, Frank Saskia, Bisio Antonella, Lenhart Dominik, Gruber Rudolf, Yates Edwin A, Richter Ralf P, Guerrini Marco, Wegner Seraphine V, Grobe Kay
Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Waldeyerstrasse 15, D-48149, Münster, Germany.
Istituto di Ricerche Chimiche e Biochimiche "G. Ronzoni", Via Giuseppe Colombo 81, Milano, 20133, Italy.
Sci Rep. 2024 Dec 31;14(1):32174. doi: 10.1038/s41598-024-84276-5.
The heparan sulfate (HS)-rich extracellular matrix (ECM) serves as an initial interaction site for the homotrimeric spike (S) protein of SARS-CoV-2 to facilitate subsequent docking to angiotensin-converting enzyme 2 (ACE2) receptors and cellular infection. More recent variants, notably Omicron, have evolved by swapping several amino acids to positively charged residues to enhance the interaction of the S-protein trimer with the negatively charged HS. However, these enhanced interactions may reduce Omicron's ability to move through the HS-rich ECM to effectively find ACE2 receptors and infect cells, raising the question of how to mechanistically explain HS-associated viral movement. In this work, we show that Omicron S proteins have evolved to balance HS interaction stability and dynamics, resulting in enhanced mobility on an HS-functionalized artificial matrix. This property is achieved by the ability of Omicron S-proteins to cross-link at least two HS chains, allowing direct S-protein switching between chains as a prerequisite for cell surface mobility. Optimized HS interactions can be targeted pharmaceutically, as an HS mimetic significantly suppressed surface binding and cellular infection specifically of the Omicron variant. These findings suggest a robust way to interfere with SARS-CoV-2 Omicron infection and potentially future variants.
富含硫酸乙酰肝素（HS）的细胞外基质（ECM）作为严重急性呼吸综合征冠状病毒2（SARS-CoV-2）同源三聚体刺突（S）蛋白的初始相互作用位点，以促进其随后与血管紧张素转换酶2（ACE2）受体对接并引发细胞感染。最近出现的变体，尤其是奥密克戎毒株，通过将几个氨基酸替换为带正电荷的残基而发生进化，以增强S蛋白三聚体与带负电荷的HS之间的相互作用。然而，这些增强的相互作用可能会降低奥密克戎毒株穿过富含HS的ECM以有效找到ACE2受体并感染细胞的能力，这就引发了如何从机制上解释与HS相关的病毒移动的问题。在这项研究中，我们表明奥密克戎毒株的S蛋白已经进化到能够平衡与HS相互作用的稳定性和动态性，从而在HS功能化的人工基质上具有更高的移动性。这种特性是通过奥密克戎毒株的S蛋白交联至少两条HS链的能力实现的，这使得S蛋白能够在链之间直接转换，这是其在细胞表面移动的前提条件。优化后的HS相互作用可以成为药物靶向作用的目标，因为一种HS模拟物能显著抑制奥密克戎变体的表面结合和细胞感染。这些发现提示了一种有效干扰SARS-CoV-2奥密克戎毒株感染以及未来可能出现的变体的方法。
