Abstract
The ongoing COVID-19 pandemic represents an unprecedented global health crisis. Here, we report the identification of a synthetic nanobody (sybody) pair, Sb#15 and Sb#68, that can bind simultaneously to the SARS-CoV-2 spike RBD and efficiently neutralize pseudotyped and live viruses by interfering with ACE2 interaction. Cryo-EM confirms that Sb#15 and Sb#68 engage two spatially discrete epitopes, influencing rational design of bispecific and tri-bispecific fusion constructs that exhibit up to 100- and 1,000-fold increase in neutralization potency, respectively. Cryo-EM of the sybody-spike complex additionally reveals a novel up-out RBD conformation. While resistant viruses emerge rapidly in the presence of single binders, no escape variants are observed in the presence of the bispecific sybody. The multivalent bispecific constructs further increase the neutralization potency against globally circulating SARS-CoV-2 variants of concern. Our study illustrates the power of multivalency and biparatopic nanobody fusions for the potential development of therapeutic strategies that mitigate the emergence of new SARS-CoV-2 escape mutants.
Keywords: SARS-CoV-2; escape mutants; sybodies; synthetic nanobodies; variants of concern.
【저자키워드】 SARS-CoV-2, variants of concern., escape mutants, sybodies, synthetic nanobodies, 【초록키워드】 viruses, ACE2, COVID-19 pandemic, variant, variants of concern, variants, SARS-CoV-2 Spike RBD, Health crisis, Epitopes, Health, nanobody, RBD, Therapeutic strategies, mutants, cryo-EM, fusion, therapeutic strategy, escape mutants, sybodies, synthetic nanobodies, Interaction, power, complex, neutralization potency, sybody, while, cryo, pseudotyped, mitigate, neutralize, new SARS-CoV-2, virus, increase in, reveal, engage, circulating SARS-CoV-2 variant, live virus, the SARS-CoV-2, 【제목키워드】 SARS-CoV-2 variant, drug resistance, mitigate, neutralize,