双靶点工程化结合蛋白可阻断新冠病毒感染并抑制补体激活

Abstract

Dual-targeting ALPs integrate ACE2-mimicking and lectin domains to enhance antiviral efficacy. • SBP10 and SBP16 bind SARS-CoV-2 spike protein with low-nanomolar affinity. • Broad neutralization is achieved across multiple variants, including Omicron sublineages. • ALPs suppress lectin pathway–mediated complement activation and inflammatory responses. • Treatment alleviates spike-induced lung injury and preserves vascular integrity in vivo . The rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and associated complement overactivation challenge current antiviral strategies that mainly target viral entry. This study aimed to develop dual-targeting engineered binding proteins capable of simultaneously blocking viral infection and complement activation. Two proteins, SBP10 and SBP16, were engineered by integrating an ACE2-mimicking peptide with a mannose-binding lectin (MBL) domain. Binding affinity and antiviral activity were evaluated using biochemical and functional assays, including inhibition of S protein–ACE2 interaction, neutralization of multiple SARS-CoV-2 variants, and assessment of lectin pathway–mediated complement activation. Both SBP10 and SBP16 bound the spike protein with low-nanomolar affinity and effectively blocked its interaction with ACE2. The proteins exhibited broad-spectrum neutralizing activity against several variants, including Alpha, Beta, Delta, and Omicron. Moreover, they significantly suppressed spike-induced activation of the lectin complement pathway. In vivo experiments further demonstrated that treatment with SBP10 or SBP16 markedly reduced spike protein-induced lung injury. In conclusion, SBP10 and SBP16 function as dual-targeting engineered binding proteins that inhibit viral entry while attenuating complement-mediated inflammation, highlighting a promising therapeutic strategy for controlling SARS-CoV-2 infection and its associated immune dysregulation.