德国波恩大学Florian I. Schmidt等研究人员合作发现，结构指导的多价纳米抗体可阻断SARS-CoV-2感染并抑制突变逃逸。相关论文于2021年1月12日在线发表于国际学术期刊《科学》。
研究人员开发了四个靶向SARS-CoV-2突刺蛋白受体结合域的中和纳米抗体。通过使用X射线晶体学和冷冻电子显微镜，研究人员定义了两个不同的结合表位。基于这些结构，研究人员设计了多价纳米抗体，其中和活性比单价纳米抗体提高了100倍以上。双特异性纳米抗体的融合抑制了逃逸突变体的出现。
几种纳米抗体构建体通过受体结合竞争被中和，而其他单价和双特异性纳米抗体触发了突刺融合机制的异常激活。突刺蛋白中的这些过早的构象变化阻止了进一步融合，并使病毒体丧失感染性。
据介绍，SARS-CoV-2大流行继续蔓延，并造成严重影响。为了进行被动免疫，纳米抗体相对于常规抗体具有尺寸和成本上的优势。
附：英文原文
Title: Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape
Author: Paul-Albert Koenig, Hrishikesh Das, Hejun Liu, Beate M. Kümmerer, Florian N. Gohr, Lea-Marie Jenster, Lisa D. J. Schiffelers, Yonas M. Tesfamariam, Miki Uchima, Jennifer D. Wuerth, Karl Gatterdam, Natalia Ruetalo, Maria H. Christensen, Caroline I. Fandrey, Sabine Normann, Jan M. P. Tdtmann, Steffen Pritzl, Leo Hanke, Jannik Boos, Meng Yuan, Xueyong Zhu, Jonathan L. Schmid-Burgk, Hiroki Kato, Michael Schindler, Ian A. Wilson, Matthias Geyer, Kerstin U. Ludwig, B. Martin Hllberg, Nicholas C. Wu, Florian I. Schmidt
Issue&Volume: 2021/01/12
Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to spread with devastating consequences. For passive immunization efforts, nanobodies have size and cost advantages over conventional antibodies. Here, we generated four neutralizing nanobodies that target the receptor-binding domain of the SARS-CoV-2 spike protein. We defined two distinct binding epitopes using x-ray crystallography and cryo-electron microscopy. Based on the structures, we engineered multivalent nanobodies with more than 100-fold improved neutralizing activity than monovalent nanobodies. Biparatopic nanobody fusions suppressed the emergence of escape mutants. Several nanobody constructs neutralized through receptor-binding competition, while other monovalent and biparatopic nanobodies triggered aberrant activation of the spike fusion machinery. These premature conformational changes in the spike protein forestalled productive fusion, and rendered the virions non-infectious.
DOI: 10.1126/science.abe6230
Source: https://science.sciencemag.org/content/early/2021/01/11/science.abe6230