tetano
Editor, Senior Moderator
Nat Commun
. 2026 Oct 4;17(1):11320.
doi: 10.1038/s41467-026-78126-3.
Xun Feng # 1 2 3 , Lunzhi Yuan # 4 , Lei Zhao # 2 , Lianqi Liu # 1 2 , Fei Xie 1 2 , Ming Zhou 4 , Gong Cheng 3 , Yi Guan 5 6 7 , Ningshao Xia 4 , Tong Cheng 8 , Wu Zhong 9 10 , Dian Xiao 11 12 , Xinbo Zhou 13 14 , Song Li 1 2
Affiliations Expand
Long-acting drug-Fc conjugate (CD388) has emerged as a new class of antivirals against influenza A and B, yet the mechanisms governing how Fc conjugation reshapes small-molecule function remain undefined. Here we establish a programmable multivalent antiviral conjugates (AVCs) platform by click chemistry that enables flexible combination of valencies and conjugated drugs, allowing systematic interrogation of valency-dependent antiviral mechanisms. Using zanamivir as a model, mono-, di-, and trivalent zanamivir are conjugated with Fc, with trivalent zanamivir-Fc conjugates (AVC-Z3) exhibiting higher activity than lower-valent AVCs. AVC-Z3 induces inter-virion aggregation, thereby coupling blockade of viral entry with restriction of viral release. This cross-linking-mediated dual-stage inhibition represents a mechanistic shift from neuraminidase suppression to physical viral immobilization. Furthermore, trivalent peramivir-Fc conjugate (AVC-P3) is synthesised and exhibits stronger antiviral activity than AVC-Z3 in vitro, with much longer half-life in vivo than AVC-Z3, and CD388 with YTE mutation. The in vivo antivirus efficacy of AVC-P3 surpasses other AVCs, baloxavir, and CD388 in H1N1-, H3N2-, H5N1-, and influenza B-infection mice models. Together, our findings define ligand valency as a determinant of antiviral mechanism.
. 2026 Oct 4;17(1):11320.
doi: 10.1038/s41467-026-78126-3.
Multivalent antiviral conjugates enhance activity against Influenza via cross-linking viruses
Xun Feng # 1 2 3 , Lunzhi Yuan # 4 , Lei Zhao # 2 , Lianqi Liu # 1 2 , Fei Xie 1 2 , Ming Zhou 4 , Gong Cheng 3 , Yi Guan 5 6 7 , Ningshao Xia 4 , Tong Cheng 8 , Wu Zhong 9 10 , Dian Xiao 11 12 , Xinbo Zhou 13 14 , Song Li 1 2
Affiliations Expand
- PMID: 42967946
- PMCID: PMC13724737
- DOI: 10.1038/s41467-026-78126-3
Abstract
Long-acting drug-Fc conjugate (CD388) has emerged as a new class of antivirals against influenza A and B, yet the mechanisms governing how Fc conjugation reshapes small-molecule function remain undefined. Here we establish a programmable multivalent antiviral conjugates (AVCs) platform by click chemistry that enables flexible combination of valencies and conjugated drugs, allowing systematic interrogation of valency-dependent antiviral mechanisms. Using zanamivir as a model, mono-, di-, and trivalent zanamivir are conjugated with Fc, with trivalent zanamivir-Fc conjugates (AVC-Z3) exhibiting higher activity than lower-valent AVCs. AVC-Z3 induces inter-virion aggregation, thereby coupling blockade of viral entry with restriction of viral release. This cross-linking-mediated dual-stage inhibition represents a mechanistic shift from neuraminidase suppression to physical viral immobilization. Furthermore, trivalent peramivir-Fc conjugate (AVC-P3) is synthesised and exhibits stronger antiviral activity than AVC-Z3 in vitro, with much longer half-life in vivo than AVC-Z3, and CD388 with YTE mutation. The in vivo antivirus efficacy of AVC-P3 surpasses other AVCs, baloxavir, and CD388 in H1N1-, H3N2-, H5N1-, and influenza B-infection mice models. Together, our findings define ligand valency as a determinant of antiviral mechanism.