Jintao Zou, Lingyu Su, Jiansheng Lu, Haiming Jing, Jiahang Liu, Xiaoqiang Zeng, Menghan Ma, De Zhao, Jun Zhang, Zhang Zhang, Jinyong Zhang, Xiaopeng Zhang
Continuous mutation of viruses enables evasion of established immune defenses and therapeutics. Here we report a broad-spectrum therapeutic design, termed HRBD, that mimics viral invasion-associated molecular patterns. HRBD demonstrated potent and broad-spectrum inhibition against Pangolin-CoV, SARS-CoV, SARS-CoV-2, and its variants, lowering the half-maximal inhibitory concentration (IC50) by approximately 1000-fold compared to the monomeric RBD. Furthermore, HRBD effectively suppressed syncytium formation induced by the spike proteins of sarbecoviruses, an effect not observed with the monomeric RBD. In hACE2-transgenic mice challenged with SARS-CoV-2, intranasal administration of HRBD reduced viral loads in lung and tracheal tissues by ∼106-fold, with no detectable immunogenicity. Binding analyses revealed that HRBD achieved approximately 1000-fold stronger avidity for hACE2 compared to the RBD monomer, superior to the high-affinity RBD-62 mutant generated by directed evolution, without affecting hACE2 enzymatic activity or subcellular localization. Oligomerization characterization confirmed that HRBD predominantly formed heptamers, visualized as ∼10 nm diameter rings via transmission electron microscopy. This mimicking strategy offers a viable approach for developing broad-spectrum therapeutics against current and future antigenically variable viruses.