Lyles Kristin V, Stone Shannon, Singh Priti, Patterson Lila D, Natekar Janhavi, Pathak Heather, Varshnaya Rohit K, Elsharkawy Amany, Liu Dongning, Bansal Shubham, Faniyi Oluwafoyinsola O, Tang Sijia, Yang Xiaoxiao, Mulpuri Nagaraju, Hamelberg Donald, Kang Congbao, Wang Binghe, Kumar Mukesh, Luo Ming
Department of Chemistry, Georgia State University, Atlanta, GA 35302, USA.
Department of Biology, Georgia State University, Atlanta, GA 35302, USA.
Viruses. 2025 Jul 16;17(7):989. doi: 10.3390/v17070989.
Despite current vaccines and therapeutics targeting SARS-CoV-2, the causative agent of the COVID-19 pandemic, cases remain high causing a burden on health care systems. Spike-protein mediated membrane fusion of SARS-CoV-2 is a critical step in viral entry. Herein, we describe entry inhibitors identified by first screening a library of about 160 compounds and then analogue synthesis. Specifically, compound was found to inhibit SARS-CoV-2 infection in a tissue model with IC of 0.3 µM. Using NMR, we found that interacts with key residues in the aromatic-rich region of the spike protein directly next to the transmembrane domain. Molecular dynamic simulations of the binding pocket in the spike protein was also mapped to the transmembrane domain, consistent with NMR findings. The amino acids in the binding site are conserved among different coronaviruses known to infect humans; therefore, inhibitors targeting this conserved binding site could be a useful addition to current therapeutics and may have pan-coronavirus antiviral activities.
尽管目前有针对2019冠状病毒病大流行的病原体严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的疫苗和疗法，但病例数仍然居高不下，给医疗系统带来负担。SARS-CoV-2的刺突蛋白介导的膜融合是病毒进入的关键步骤。在此，我们描述了通过首先筛选约160种化合物的文库然后进行类似物合成而鉴定出的进入抑制剂。具体而言，发现化合物在组织模型中抑制SARS-CoV-2感染，半数抑制浓度（IC）为0.3µM。使用核磁共振（NMR），我们发现该化合物与跨膜结构域旁边刺突蛋白富含芳香族区域的关键残基相互作用。刺突蛋白中该化合物结合口袋的分子动力学模拟也定位到跨膜结构域，与核磁共振结果一致。已知感染人类的不同冠状病毒之间，结合位点的氨基酸是保守的；因此，靶向这个保守结合位点的抑制剂可能是当前疗法的有益补充，并且可能具有泛冠状病毒抗病毒活性。
