The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, Key Laboratory of Chemical Biology of Fujian Province, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China.
State Key Laboratory for Emerging Infectious Diseases and InnoHK Centre for Infectious Diseases, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
ACS Nano. 2022 Sep 27;16(9):15310-15317. doi: 10.1021/acsnano.2c06803. Epub 2022 Sep 8.
Natural ligand-receptor interactions that play pivotal roles in biological events are ideal models for design and assembly of artificial recognition molecules. Herein, aiming at the structural characteristics of the spike trimer and infection mechanism of SARS-CoV-2, we have designed a DNA framework-guided spatial-patterned neutralizing aptamer trimer for SARS-CoV-2 neutralization. The ∼5.8 nm tetrahedral DNA framework affords precise spatial organization and matched valence as four neutralizing aptamers (MATCH-4), which matches with nanometer precision the topmost surface of SARS-CoV-2 spike trimer, enhancing the interaction between MATCH-4 and spike trimer. Moreover, the DNA framework provides a dimensionally complementary nanoscale barrier to prevent the spike trimer-ACE2 interaction and the conformational transition, thereby inhibiting SARS-CoV-2-host cell fusion and infection. As a result, the spatial- and valence-matched MATCH-4 ensures improved binding affinity and neutralizing activity against SARS-CoV-2 and its varied mutant strains, particularly the current Omicron variant, that are evasive of the majority of existing neutralizing antibodies. In addition, because neutralizing aptamers specific to other targets can be evolved and assembled, the present design has the potential to inhibit other wide-range and emerging pathogens.
天然配体-受体相互作用在生物事件中起着关键作用，是设计和组装人工识别分子的理想模型。在此，针对 SARS-CoV-2 刺突三聚体的结构特征和感染机制，我们设计了一种 DNA 框架引导的空间图案中和性适体三聚体用于 SARS-CoV-2 的中和。约 5.8nm 的四面体 DNA 框架提供了精确的空间组织和匹配的价态作为四个中和适体（MATCH-4），与 SARS-CoV-2 刺突三聚体的最顶端表面精确匹配，增强了 MATCH-4 与刺突三聚体之间的相互作用。此外，DNA 框架提供了一个维度互补的纳米级屏障，以防止刺突三聚体与 ACE2 的相互作用和构象转变，从而抑制 SARS-CoV-2 与宿主细胞的融合和感染。结果表明，空间和价态匹配的 MATCH-4 确保了对 SARS-CoV-2 及其多种突变株的结合亲和力和中和活性的提高，特别是目前逃避大多数现有中和抗体的奥密克戎变异株。此外，由于可以进化和组装针对其他靶标的中和适体，因此本设计有可能抑制其他广谱和新兴的病原体。
