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

Overview

Journal Elife

Date 2025 Jan 16

PMID 39817728

Authors

Bin Zheng

Meimei Duan

Yifen Huang

Shangchen Wang

Jun Qiu

Zhuojian Lu

Lichao Liu

Guojin Tang

Lin Cheng

Peng Zheng

Affiliations

Soon will be listed here.

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 , 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.

References

Lin C, Chung C, Heine H, Chang W . Vaccinia virus envelope H3L protein binds to cell surface heparan sulfate and is important for intracellular mature virion morphogenesis and virus infection in vitro and in vivo. J Virol. 2000; 74(7):3353-65. PMC: 111837. DOI: 10.1128/jvi.74.7.3353-3365.2000. View

Phillips J, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E . Scalable molecular dynamics with NAMD. J Comput Chem. 2005; 26(16):1781-802. PMC: 2486339. DOI: 10.1002/jcc.20289. View

Vakaniaki E, Kacita C, Kinganda-Lusamaki E, OToole A, Wawina-Bokalanga T, Mukadi-Bamuleka D . Sustained human outbreak of a new MPXV clade I lineage in eastern Democratic Republic of the Congo. Nat Med. 2024; 30(10):2791-2795. PMC: 11485229. DOI: 10.1038/s41591-024-03130-3. View

Grater F, Shen J, Jiang H, Gautel M, Grubmuller H . Mechanically induced titin kinase activation studied by force-probe molecular dynamics simulations. Biophys J. 2004; 88(2):790-804. PMC: 1305156. DOI: 10.1529/biophysj.104.052423. View

OToole A, Neher R, Ndodo N, Borges V, Gannon B, Gomes J . APOBEC3 deaminase editing in mpox virus as evidence for sustained human transmission since at least 2016. Science. 2023; 382(6670):595-600. PMC: 10880385. DOI: 10.1126/science.adg8116. View

Yu J, Zhang X, Liu J, Xiang L, Huang S, Xie X . Phylogeny and molecular evolution of the first local monkeypox virus cluster in Guangdong Province, China. Nat Commun. 2023; 14(1):8241. PMC: 10716143. DOI: 10.1038/s41467-023-44092-3. View

Lin Z, Akin H, Rao R, Hie B, Zhu Z, Lu W . Evolutionary-scale prediction of atomic-level protein structure with a language model. Science. 2023; 379(6637):1123-1130. DOI: 10.1126/science.ade2574. View

Alsteens D, Newton R, Schubert R, Martinez-Martin D, Delguste M, Roska B . Nanomechanical mapping of first binding steps of a virus to animal cells. Nat Nanotechnol. 2016; 12(2):177-183. DOI: 10.1038/nnano.2016.228. View

Watson J, Juergens D, Bennett N, Trippe B, Yim J, Eisenach H . De novo design of protein structure and function with RFdiffusion. Nature. 2023; 620(7976):1089-1100. PMC: 10468394. DOI: 10.1038/s41586-023-06415-8. View

10.

Deng Y, Wu T, Wang M, Shi S, Yuan G, Li X . Enzymatic biosynthesis and immobilization of polyprotein verified at the single-molecule level. Nat Commun. 2019; 10(1):2775. PMC: 6591319. DOI: 10.1038/s41467-019-10696-x. View

11.

Goktas M, Luo C, Sullan R, Bergues-Pupo A, Lipowsky R, Vila Verde A . Molecular mechanics of coiled coils loaded in the shear geometry. Chem Sci. 2018; 9(20):4610-4621. PMC: 5969510. DOI: 10.1039/c8sc01037d. View

12.

Wang J, Shahed-Ai-Mahmud M, Chen A, Li K, Tan H, Joyce R . An Overview of Antivirals against Monkeypox Virus and Other Orthopoxviruses. J Med Chem. 2023; 66(7):4468-4490. DOI: 10.1021/acs.jmedchem.3c00069. View

13.

Muller D, Helenius J, Alsteens D, Dufrene Y . Force probing surfaces of living cells to molecular resolution. Nat Chem Biol. 2009; 5(6):383-90. DOI: 10.1038/nchembio.181. View

14.

Moss B . Investigating Viruses During the Transformation of Molecular Biology: Part II. Annu Rev Virol. 2020; 7(1):15-36. DOI: 10.1146/annurev-virology-021020-100558. View

15.

Eberhardt J, Santos-Martins D, Tillack A, Forli S . AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings. J Chem Inf Model. 2021; 61(8):3891-3898. PMC: 10683950. DOI: 10.1021/acs.jcim.1c00203. View

16.

Podduturi S, Vemula D, Singothu S, Bhandari V . investigation of E8 surface protein of the monkeypox virus to identify potential therapeutic agents. J Biomol Struct Dyn. 2023; 42(16):8242-8255. DOI: 10.1080/07391102.2023.2245041. View

17.

Baek M, McHugh R, Anishchenko I, Jiang H, Baker D, DiMaio F . Accurate prediction of protein-nucleic acid complexes using RoseTTAFoldNA. Nat Methods. 2023; 21(1):117-121. PMC: 10776382. DOI: 10.1038/s41592-023-02086-5. View

18.

Cao Y, Lam C, Wang M, Li H . Nonmechanical protein can have significant mechanical stability. Angew Chem Int Ed Engl. 2005; 45(4):642-5. DOI: 10.1002/anie.200502623. View

19.

Da Fonseca F, Wolffe E, WEISBERG A, Moss B . Effects of deletion or stringent repression of the H3L envelope gene on vaccinia virus replication. J Virol. 2000; 74(16):7518-28. PMC: 112272. DOI: 10.1128/jvi.74.16.7518-7528.2000. View

20.

Brooks 3rd C, MacKerell Jr A, Post C, Nilsson L . Biomolecular dynamics in the 21st century. Biochim Biophys Acta Gen Subj. 2023; 1868(2):130534. PMC: 10842176. DOI: 10.1016/j.bbagen.2023.130534. View