Affiliation:
1. State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University
2. Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital
Abstract
The 2022 global outbreak of mpox virus (MPXV), recognized as a public health emergency by the World Health Organization (WHO), underscored the urgent need for specific antiviral agents. H3, a key antiviral target, mediates the adhesion of MPXV to host cells through its interaction with heparan sulfate (HS). Understanding the details of the H3-HS interaction has been challenging due to the highly flexible and complex nature of HS, which hinders its structural characterization. Utilizing state-of-the-art computational biology techniques, including molecular dynamics (MD) simulations, dynamic molecular docking, and AlphaFold2, we identified a novel α-helical domain in H3 critical for HS binding. This domain, conserved across
orthopoxviruses
, was validated experimentally, confirming its crucial role in viral adhesion at both molecular and cellular levels. Targeting this newly discovered HS-binding domain, we
de novo
designed a protein inhibitor, AI-PoxBlock723, which effectively disrupt the H3-HS interaction, and inhibit viral infection. Our work not only introduces a promising anti-poxviral drug candidate, but also provides a comprehensive framework for elucidating complex protein-glycan interactions.
Publisher
eLife Sciences Publications, Ltd