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Peer-reviewedCC BY-NC-ND 4.0Cell Reports Medicine

Punicalin targets RSV glycoprotein and fusion protein at non-overlapping sites to prevent viral escape

  • Yingcai Xiong1,2
  • Jingyi Ming1
  • Zhaowei Zhang1
  • Jiru Zhang1
  • Xiaoqing Zhou1
  • Biyu Cao1
  • Guang Li3
  • Yuqing Zhu1
  • Zepeng Yang1
  • Junxi Song1
  • Zhao Wang1
  • Mei Chen1
3 more authors
  • Keyu Tao1
  • Yue Kang3
  • Jianjian Ji1,4
4 affiliations
  1. 1Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, The First Clinical College, Nanjing University of Chinese Medicine, Nanjing, China
  2. 2The State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China
  3. 3School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
  4. 4Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Zhongnan West Road, Wuxi 214071, China
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Abstract

Respiratory syncytial virus (RSV) causes substantial respiratory disease, while treatment is limited by drug resistance. Molecular docking of a 3,880-compound natural-product library identifies punicalin (PUN) as a dual-target RSV entry inhibitor. PUN inhibits the evaluated RSV-A and RSV-B strains, including a clinical isolate, and retains activity against strains resistant to ziresovir, ribavirin, nirsevimab, and palivizumab. After 20 passages under PUN selection, the half-maximal inhibitory concentration (IC50) increases 3.88-fold, remaining below the predefined >10-fold resistance threshold. Mechanistic analyses suggest that PUN interacts with the G protein cystine-noose region involving N178, N179, and W183 to inhibit attachment and with an F protein region involving V243, T245, and P246 to stabilize prefusion F and inhibit membrane fusion. These regions do not overlap known resistance hotspots. In RSV-infected mice, nebulized PUN provides sustained respiratory exposure, reduces lung viral loads and pathology, and attenuates inflammatory responses.

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Cite

BibTeXRIS
BibTeX
@article{xiong2026punicalin,
  title = {{Punicalin targets RSV glycoprotein and fusion protein at non-overlapping sites to prevent viral escape}},
  author = {Yingcai Xiong and Jingyi Ming and Zhaowei Zhang and Jiru Zhang and Xiaoqing Zhou and Biyu Cao and Guang Li and Yuqing Zhu and Zepeng Yang and Junxi Song and Zhao Wang and Mei Chen and Keyu Tao and Yue Kang and Jianjian Ji},
  journal = {Cell Reports Medicine},
  year = {2026},
  month = sep,
  doi = {10.1016/j.xcrm.2026.103078},
  url = {https://doi.org/10.1016/j.xcrm.2026.103078},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Punicalin targets RSV glycoprotein and fusion protein at non-overlapping sites to prevent viral escape
AU  - Yingcai Xiong
AU  - Jingyi Ming
AU  - Zhaowei Zhang
AU  - Jiru Zhang
AU  - Xiaoqing Zhou
AU  - Biyu Cao
AU  - Guang Li
AU  - Yuqing Zhu
AU  - Zepeng Yang
AU  - Junxi Song
AU  - Zhao Wang
AU  - Mei Chen
AU  - Keyu Tao
AU  - Yue Kang
AU  - Jianjian Ji
PY  - 2026
DA  - 2026/09/25
JO  - Cell Reports Medicine
DO  - 10.1016/j.xcrm.2026.103078
UR  - https://doi.org/10.1016/j.xcrm.2026.103078
AB  - Respiratory syncytial virus (RSV) causes substantial respiratory disease, while treatment is limited by drug resistance. Molecular docking of a 3,880-compound natural-product library identifies punicalin (PUN) as a dual-target RSV entry inhibitor. PUN inhibits the evaluated RSV-A and RSV-B strains, including a clinical isolate, and retains activity against strains resistant to ziresovir, ribavirin, nirsevimab, and palivizumab. After 20 passages under PUN selection, the half-maximal inhibitory concentration (IC50) increases 3.88-fold, remaining below the predefined >10-fold resistance threshold. Mechanistic analyses suggest that PUN interacts with the G protein cystine-noose region involving N178, N179, and W183 to inhibit attachment and with an F protein region involving V243, T245, and P246 to stabilize prefusion F and inhibit membrane fusion. These regions do not overlap known resistance hotspots. In RSV-infected mice, nebulized PUN provides sustained respiratory exposure, reduces lung viral loads and pathology, and attenuates inflammatory responses.
SN  - 2666-3791
ER  -