Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Department of Pediatrics, Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Structure. 2021 Sep 2;29(9):951-962.e3. doi: 10.1016/j.str.2021.04.005. Epub 2021 Apr 29.
We recently discovered a superantigen-like motif sequentially and structurally similar to a staphylococcal enterotoxin B (SEB) segment, near the S1/S2 cleavage site of the SARS-CoV-2 spike protein, which might explain the multisystem inflammatory syndrome (MIS-C) observed in children and the cytokine storm in severe COVID-19 patients. We show here that an anti-SEB monoclonal antibody (mAb), 6D3, can bind this viral motif at its polybasic (PRRA) insert to inhibit infection in live virus assays. The overlap between the superantigenic site of the spike and its proteolytic cleavage site suggests that the mAb prevents viral entry by interfering with the proteolytic activity of cell proteases (furin and TMPRSS2). The high affinity of 6D3 for this site originates from a polyacidic segment at its heavy chain CDR2. The study points to the potential utility of 6D3 for possibly treating COVID-19, MIS-C, or common colds caused by human coronaviruses that also possess a furin-like cleavage site.
我们最近在 SARS-CoV-2 刺突蛋白的 S1/S2 裂解位点附近发现了一个与葡萄球菌肠毒素 B (SEB) 片段在序列和结构上相似的超级抗原样基序，这可能可以解释在儿童中观察到的多系统炎症综合征 (MIS-C) 和重症 COVID-19 患者中的细胞因子风暴。我们在这里表明，一种抗 SEB 单克隆抗体 (mAb)，6D3，可以结合该病毒基序的多碱性 (PRRA) 插入物，以在活病毒测定中抑制感染。刺突的超抗原位点与其蛋白水解裂解位点之间的重叠表明，该 mAb 通过干扰细胞蛋白酶 (弗林和 TMPRSS2) 的蛋白水解活性来阻止病毒进入。6D3 对该位点的高亲和力源自其重链 CDR2 中的多酸性片段。该研究表明，6D3 可能具有治疗 COVID-19、MIS-C 或由也具有类似弗林蛋白酶裂解位点的人类冠状病毒引起的普通感冒的潜力。
