Esparza Thomas J, Chen Yaozong, Martin Negin P, Bielefeldt-Ohmann Helle, Bowen Richard A, Tolbert William D, Pazgier Marzena, Brody David L
The National Institute of Neurological Disorders and Stroke Intramural Research Program, Laboratory of Functional and Molecular Imaging, Bethesda, MD, USA 20892.
Center for Neuroscience and Regenerative Medicine, Uniformed Services University, Bethesda, MD, USA 20817.
bioRxiv. 2021 Nov 12:2021.11.10.468147. doi: 10.1101/2021.11.10.468147.
There remains an unmet need for globally deployable, low-cost therapeutics for the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Previously, we reported on the isolation and characterization of a potent single-domain nanobody, NIH-CoVnb-112, specific for the receptor binding domain (RBD) of SARS-CoV-2. Here, we report on the molecular basis for the observed broad neutralization capability of NIH-CoVnb-112 against variant SARS-CoV-2 pseudoviruses, including the currently dominant Delta variant. The structure of NIH-CoVnb-112 bound to SARS-CoV-2 RBD reveals a large contact surface area overlapping the angiotensin converting enzyme 2 (ACE2) binding site, which is largely unencumbered by the common RBD mutations. In an pilot study, we demonstrate effective reductions in weight loss, viral burden, and lung pathology in a Syrian hamster model of COVID-19 following nebulized delivery of NIH-CoVnb-112. These findings support the further development of NIH-CoVnb-112 as a potential adjunct preventative therapeutic for the treatment of SARS-CoV-2 infection.
对于正在肆虐的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）大流行，全球范围内仍迫切需要可广泛部署的低成本治疗方法。此前，我们报道了一种针对SARS-CoV-2受体结合域（RBD）的强效单域纳米抗体NIH-CoVnb-112的分离和特性。在此，我们报告了NIH-CoVnb-112对变异SARS-CoV-2假病毒（包括当前占主导地位的德尔塔变异株）具有广泛中和能力的分子基础。与SARS-CoV-2 RBD结合的NIH-CoVnb-112的结构显示出一个与血管紧张素转换酶2（ACE2）结合位点重叠的大接触表面积，而该位点在很大程度上不受常见RBD突变的影响。在一项初步研究中，我们证明了在雾化递送NIH-CoVnb-112后，新冠病毒疾病（COVID-19）叙利亚仓鼠模型的体重减轻、病毒载量和肺部病理状况得到有效改善。这些发现支持将NIH-CoVnb-112进一步开发为治疗SARS-CoV-2感染的潜在辅助预防性治疗药物。
