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PreprintCited by 3Poxvirus research and outbreaksvaccines and immunoinformatics approachesComputational Drug Discovery Methods

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Discovery of a Heparan Sulfate Binding Domain in Monkeypox Virus H3 as an Anti-poxviral Drug Target Combining AI and MD Simulations

Open access
Zheng, Bin, Duan, Meimei, Huang, Yifen, Wang, Shangchen, Qiu, Jun, Lu, Zhuojian, Liu, Lichao, Tang, Guojin, Cheng, Lin, Zheng, Peng·2024·eLife
DOI 10.1101/2024.06.26.600898

Preprint — published as 10.7554/elife.100545.3

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Abstract

Viral adhesion to host cells is a critical step in infection for many viruses, including monkeypox virus (MPXV). In MPXV, the H3 protein mediates viral adhesion through its interaction with heparan sulfate (HS), yet the structural details of this interaction have remained elusive. Using AI-based structural prediction tools and molecular dynamics (MD) simulations, we identified a novel, positively charged α-helical domain in H3 that is essential for HS binding. This conserved domain, found across orthopoxviruses , was experimentally validated and shown to be critical for viral adhesion, making it an ideal target for antiviral drug development. Targeting this domain, we designed a protein inhibitor, which disrupted the H3-HS interaction, inhibited viral infection in vitro and viral replication in vivo , offering a promising antiviral candidate. Our findings reveal a novel therapeutic target of MPXV, demonstrating the potential of combination of AI-driven methods and MD simulations to accelerate antiviral drug discovery.

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Metadata

Authors
Zheng, B., Duan, M., Huang, Y., Wang, S., Qiu, J., Lu, Z., Liu, L., Tang, G., Cheng, L., & Zheng, P.
Affiliations
  • Nanjing University (CN)
  • Shenzhen Third People’s Hospital (CN)
  • Nanjing Drum Tower Hospital (CN)
Corresponding author
Zheng, Peng
ORCID
Venue
eLife
Publisher
openRxiv
Published
2024-06-28
Volume
13
ISSN
2050-084X (ISSN-L)
DOI
10.1101/2024.06.26.600898
OpenAlex
W4406431738
Cited by
3
References
2
Citations by year
2026: 2 · 2025: 1
FWCI
1.51
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
Funders
  • National Natural Science Foundation of China (22477058, 22222703)
  • Natural Science Foundation of Jiangsu Province (BK20202004)
  • Fundamental Research Funds for the Central Universities (020514380335)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › Poxvirus research and outbreaks
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
Keywords
monkeypox virus, heparan sulfate binding, viral attachment, orthopoxvirus, antiviral drug targets, molecular dynamics simulation, viral replication inhibition

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