Pei Gaofeng, Xu Weifan, Lan Jun, Wang Xinquan, Li Pilong
Beijing Advanced Innovation Center for Structural Biology and Frontier Research Center for Biological Structure, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Fundam Res. 2022 Mar 3;2(4):562-569. doi: 10.1016/j.fmre.2022.01.034. eCollection 2022 Jul.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, causing COVID-19, is the most challenging pandemic of the modern era. It has resulted in over 5 million deaths worldwide. To quickly explore therapeutics for COVID-19, we utilized a previously-established system, namely CEBIT. We performed a high-throughput screening of FDA-approved drugs to inhibit the interaction between the receptor-binding domain (RBD) of SARS-CoV-2 spike protein and its obligate receptor ACE2. This interaction is essential for viral entry and therefore represents a promising therapeutic target. Based on the recruitment of interacting molecules into phase-separated condensates as a readout, we identified six positive candidates from a library of 2572 compounds, most of which have been reported to inhibit the entry of SARS-CoV-2 into host cells. Our surface plasmon resonance (SPR) and molecular docking analyses revealed the possible mechanisms via which these compounds interfere with the interaction between RBD and ACE2. Hence, our results indicate that CEBIT is highly versatile for identifying drugs against SARS-CoV-2 entry, and targeting CoV-2 entry by small molecule drugs is a viable therapeutic option to treat COVID-19 in addition to commonly used monoclonal antibodies.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染导致了COVID-19，这是现代最具挑战性的大流行疾病。它已在全球造成超过500万人死亡。为了快速探索针对COVID-19的治疗方法，我们利用了一个先前建立的系统，即CEBIT。我们对美国食品药品监督管理局（FDA）批准的药物进行了高通量筛选，以抑制SARS-CoV-2刺突蛋白的受体结合域（RBD）与其必需受体血管紧张素转换酶2（ACE2）之间的相互作用。这种相互作用对于病毒进入至关重要，因此是一个有前景的治疗靶点。基于将相互作用分子招募到相分离凝聚物中作为读数，我们从2572种化合物的文库中鉴定出6种阳性候选物，其中大多数已被报道可抑制SARS-CoV-2进入宿主细胞。我们的表面等离子体共振（SPR）和分子对接分析揭示了这些化合物干扰RBD与ACE2之间相互作用的可能机制。因此，我们的结果表明，CEBIT在鉴定针对SARS-CoV-2进入的药物方面具有高度通用性，并且除了常用的单克隆抗体外，通过小分子药物靶向CoV-2进入是治疗COVID-19的一种可行治疗选择。
