Kim Sang Hoon, Kearns Fiona L, Rosenfeld Mia A, Votapka Lane, Casalino Lorenzo, Papanikolas Micah, Amaro Rommie E, Freeman Ronit
Department of Applied Physical Sciences, University of North Carolina - Chapel Hill, 1112 Murray Hall, CB#3050, Chapel Hill, NC 27599-2100, USA.
Department of Chemistry and Biochemistry, University of California, San Diego, 4238 Urey Hall, MC-0340, La Jolla, CA 92093-0340, USA.
Cell Rep Phys Sci. 2023 Apr 19;4(4):101346. doi: 10.1016/j.xcrp.2023.101346. Epub 2023 Apr 7.
Viral variants of concern continue to arise for SARS-CoV-2, potentially impacting both methods for detection and mechanisms of action. Here, we investigate the effect of an evolving spike positive charge in SARS-CoV-2 variants and subsequent interactions with heparan sulfate and the angiotensin converting enzyme 2 (ACE2) in the glycocalyx. We show that the positively charged Omicron variant evolved enhanced binding rates to the negatively charged glycocalyx. Moreover, we discover that while the Omicron spike-ACE2 affinity is comparable to that of the Delta variant, the Omicron spike interactions with heparan sulfate are significantly enhanced, giving rise to a ternary complex of spike-heparan sulfate-ACE2 with a large proportion of double-bound and triple-bound ACE2. Our findings suggest that SARS-CoV-2 variants evolve to be more dependent on heparan sulfate in viral attachment and infection. This discovery enables us to engineer a second-generation lateral-flow test strip that harnesses both heparin and ACE2 to reliably detect all variants of concern, including Omicron.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）仍在不断出现值得关注的病毒变种，这可能会对检测方法和作用机制产生影响。在此，我们研究了SARS-CoV-2变种中不断演变的刺突蛋白正电荷的影响，以及随后与硫酸乙酰肝素和糖萼中的血管紧张素转换酶2（ACE2）的相互作用。我们发现，带正电荷的奥密克戎变种与带负电荷的糖萼的结合速率有所提高。此外，我们还发现，虽然奥密克戎刺突蛋白与ACE2的亲和力与德尔塔变种相当，但奥密克戎刺突蛋白与硫酸乙酰肝素的相互作用显著增强，形成了刺突蛋白-硫酸乙酰肝素-ACE2三元复合物，其中大部分ACE2为双结合和三结合形式。我们的研究结果表明，SARS-CoV-2变种在病毒附着和感染过程中对硫酸乙酰肝素的依赖性越来越强。这一发现使我们能够设计出一种第二代侧流检测试纸条，利用肝素和ACE2来可靠地检测包括奥密克戎在内的所有值得关注的变种。
