Multivalent antiviral conjugates enhance activity against Influenza via cross-linking viruses

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.

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Cite

BibTeX RIS

BibTeX

@article{feng2026multivalent,
  title = {{Multivalent antiviral conjugates enhance activity against Influenza via cross-linking viruses}},
  author = {Xun Feng and Lunzhi Yuan and Lei Zhao and Lianqi Liu and Fei Xie and Ming Zhou and Gong Cheng and Yi Guan and Ningshao Xia and Tong Cheng and Wu Zhong and Dian Xiao and Xinbo Zhou and Song Li},
  journal = {Nature Communications},
  year = {2026},
  month = oct,
  doi = {10.1038/s41467-026-78126-3},
  url = {https://www.nature.com/articles/s41467-026-78126-3},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - Multivalent antiviral conjugates enhance activity against Influenza via cross-linking viruses
AU  - Xun Feng
AU  - Lunzhi Yuan
AU  - Lei Zhao
AU  - Lianqi Liu
AU  - Fei Xie
AU  - Ming Zhou
AU  - Gong Cheng
AU  - Yi Guan
AU  - Ningshao Xia
AU  - Tong Cheng
AU  - Wu Zhong
AU  - Dian Xiao
AU  - Xinbo Zhou
AU  - Song Li
PY  - 2026
DA  - 2026/10/04
JO  - Nature Communications
DO  - 10.1038/s41467-026-78126-3
UR  - https://www.nature.com/articles/s41467-026-78126-3
AB  - 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.
SN  - 2041-1723
ER  -

Abstract

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