空间和价态匹配的中和 DNA 纳米结构可阻止野生型 SARS-CoV-2 和 Omicron 变异体感染,ACS Nano

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空间和价态匹配的中和 DNA 纳米结构可阻止野生型 SARS-CoV-2 和 Omicron 变异体感染
ACS Nano ( IF 15.8 ) Pub Date : 2022-09-08 , DOI: 10.1021/acsnano.2c06803
Shuang Wan ₁ , Siwen Liu ₂ , Miao Sun ₁ , Jialu Zhang _{1,

3} , Xinyu Wei ₁ , Ting Song ₁ , Yuhao Li ₁ , Xinyang Liu ₁ , Honglin Chen ₂ , Chaoyong James Yang _{1,

3} , Yanling Song ₁

Affiliation

在生物事件中发挥关键作用的天然配体-受体相互作用是人工识别分子设计和组装的理想模型。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适体三聚体，用于中和SARS-CoV-2。∼5.8 nm 四面体 DNA 框架提供了精确的空间组织和匹配价作为四个中和适体 (MATCH-4)，它以纳米精度与 SARS-CoV-2 刺突三聚体的最上表面相匹配，增强了 MATCH-4 和刺突之间的相互作用三聚体。此外，DNA框架提供了尺寸互补的纳米级屏障，以防止刺突三聚体-ACE2相互作用和构象转变，从而抑制SARS-CoV-2-宿主细胞融合和感染。因此，空间和价态匹配的 MATCH-4 可确保针对 SARS-CoV-2 及其各种突变株（特别是当前的 Omicron 变种）提高结合亲和力和中和活性，这些突变株可避开大多数现有中和抗体。此外，由于可以进化和组装针对其他靶标的中和适体，因此本设计具有抑制其他广泛和新兴病原体的潜力。

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Spatial- and Valence-Matched Neutralizing DNA Nanostructure Blocks Wild-Type SARS-CoV-2 and Omicron Variant Infection

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.

更新日期：2022-09-08

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