加速PERx反应可实现用于有效中和SARS-CoV-2及其变体的共价纳米抗体。
Accelerating PERx reaction enables covalent nanobodies for potent neutralization of SARS-CoV-2 and variants.
作者信息
Yu Bingchen, Li Shanshan, Tabata Takako, Wang Nanxi, Cao Li, Kumar G Renuka, Sun Wei, Liu Jun, Ott Melanie, Wang Lei
机构信息
Department of Pharmaceutical Chemistry and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
Gladstone Institutes, San Francisco, CA 94158, USA.
出版信息
Chem. 2022 Oct 13;8(10):2766-2783. doi: 10.1016/j.chempr.2022.07.012. Epub 2022 Jul 18.
The long-lasting COVID-19 pandemic and increasing SARS-CoV-2 variants demand effective drugs for prophylactics and treatment. Protein-based biologics offer high specificity, yet their noncovalent interactions often lead to drug dissociation and incomplete inhibition. Here, we have developed covalent nanobodies capable of binding with SARS-CoV-2 irreversibly via a proximity-enabled reactive therapeutic (PERx) mechanism. A latent bioreactive amino acid (FFY) was designed and genetically encoded into nanobodies to accelerate the PERx reaction rate. Compared with the noncovalent wild-type nanobody, the FFY-incorporated covalent nanobodies neutralized both wild-type SARS-CoV-2 and its Alpha, Delta, Epsilon, Lambda, and Omicron variants with drastically higher potency. This PERx-enabled covalent-nanobody strategy and the related insights into increased potency can be valuable to developing effective therapeutics for various viral infections.
长期的新冠疫情以及不断增加的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变种需要有效的预防和治疗药物。基于蛋白质的生物制剂具有高特异性，但其非共价相互作用往往导致药物解离和抑制不完全。在此，我们开发了一种共价纳米抗体，能够通过邻近激活反应性治疗（PERx）机制与SARS-CoV-2不可逆结合。设计了一种潜在的生物反应性氨基酸（FFY）并将其基因编码到纳米抗体中，以加速PERx反应速率。与非共价野生型纳米抗体相比，掺入FFY的共价纳米抗体以显著更高的效力中和野生型SARS-CoV-2及其Alpha、Delta、Epsilon、Lambda和Omicron变种。这种基于PERx的共价纳米抗体策略以及对提高效力的相关见解对于开发针对各种病毒感染的有效疗法可能具有重要价值。
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