Liu Jinxin, Luo Song, Xu Xiaole, Zhang Enhao, Liang Houde, Zhang John Z H, Duan Lili
School of Physics and Electronics, Shandong Normal University, Jinan 250014, China.
Faculty of Synthetic Biology, Shenzhen University of Advanced Technology, Shenzhen 518055, China.
J Phys Chem Lett. 2025 Jan 9;16(1):396-405. doi: 10.1021/acs.jpclett.4c03028. Epub 2024 Dec 31.
Addressing the frequent emergence of SARS-CoV-2 mutant strains requires therapeutic approaches with innovative neutralization mechanisms. The targeting of multivalent nanobodies can enhance potency and reduce the risk of viral escape, positioning them as promising drug candidates. Here, the synergistic mechanisms of the two types of nanobodies are investigated deeply. Our research revealed that the Fu2-1-Fu2-2 system exhibited significant synergy, whereas the Sb#15-Sb#68 system demonstrated antagonism, in which entropy was the dominant contributor to antagonism. Conformational analysis further demonstrated that the presence of a monomeric nanobody influenced the flexibility of residues near other epitopes, thereby affecting the overall synergy of the systems. Moreover, we identified that changes in the hydrogen bond network and the charge of residues played a critical role in the binding between nanobodies and spike. We hope this study will provide novel insights into the development of multivalent nanobody combinations.
应对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）突变株的频繁出现需要具有创新中和机制的治疗方法。靶向多价纳米抗体可以提高效力并降低病毒逃逸的风险，使其成为有前景的候选药物。在此，深入研究了两种类型纳米抗体的协同机制。我们的研究表明，Fu2-1-Fu2-2系统表现出显著的协同作用，而Sb#15-Sb#68系统表现出拮抗作用，其中熵是拮抗作用的主要贡献因素。构象分析进一步表明，单体纳米抗体的存在影响了其他表位附近残基的灵活性，从而影响了系统的整体协同作用。此外，我们发现氢键网络和残基电荷的变化在纳米抗体与刺突蛋白的结合中起关键作用。我们希望这项研究将为多价纳米抗体组合的开发提供新的见解。
