Laboratory of Viral Infection, Department of Infection Control and Immunology, Ōmura Satoshi Memorial Institute & Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
Safety Science Laboratories, Kao Corporation, Tokyo, Japan.
PLoS Pathog. 2021 Oct 14;17(10):e1009542. doi: 10.1371/journal.ppat.1009542. eCollection 2021 Oct.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the disease COVID-19 can lead to serious symptoms, such as severe pneumonia, in the elderly and those with underlying medical conditions. While vaccines are now available, they do not work for everyone and therapeutic drugs are still needed, particularly for treating life-threatening conditions. Here, we showed nasal delivery of a new, unmodified camelid single-domain antibody (VHH), termed K-874A, effectively inhibited SARS-CoV-2 titers in infected lungs of Syrian hamsters without causing weight loss and cytokine induction. In vitro studies demonstrated that K-874A neutralized SARS-CoV-2 in both VeroE6/TMPRSS2 and human lung-derived alveolar organoid cells. Unlike other drug candidates, K-874A blocks viral membrane fusion rather than viral attachment. Cryo-electron microscopy revealed K-874A bound between the receptor binding domain and N-terminal domain of the virus S protein. Further, infected cells treated with K-874A produced fewer virus progeny that were less infective. We propose that direct administration of K-874A to the lung could be a new treatment for preventing the reinfection of amplified virus in COVID-19 patients.
引起 COVID-19 疾病的严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）可导致老年人和有潜在医疗条件的人出现严重肺炎等严重症状。虽然现在有疫苗，但它们并不适用于所有人，仍需要治疗药物，特别是用于治疗危及生命的病症。在这里，我们展示了一种新的、未经修饰的骆驼科单域抗体（VHH），称为 K-874A，通过鼻腔给药，可有效抑制感染的叙利亚仓鼠肺部的 SARS-CoV-2 滴度，而不会导致体重减轻和细胞因子诱导。体外研究表明，K-874A 可中和 VeroE6/TMPRSS2 和人肺衍生肺泡类器官细胞中的 SARS-CoV-2。与其他候选药物不同，K-874A 阻断病毒膜融合，而不是病毒附着。冷冻电镜显示 K-874A 结合在病毒 S 蛋白的受体结合域和 N 端结构域之间。此外，用 K-874A 处理的受感染细胞产生的病毒后代数量更少，感染性也更低。我们提出，将 K-874A 直接施用于肺部可能是预防 COVID-19 患者体内扩增病毒再感染的新治疗方法。
