9NNU

Crystal Structure of Ebola Envelope glycoprotein GP in complex with compound LD4-189ZbR

This is a non-PDB format compatible entry.

Summary for 9NNU

• Entry DOI: 10.2210/pdb9nnu/pdb
• Descriptor: Envelope glycoprotein, GP2, alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: ebola, small molecule, drug inhibitor, glycoprotein, viral protein
• Biological source: Ebola virus - Mayinga, Zaire, 1976; More
• Total number of polymer chains: 2
• Total formula weight: 72122.61

Authors

Agrawal, S.,Wilson, I.A. (deposition date: 2025-03-06, release date: 2025-07-30)

Primary citation

Dada, L.,Nagai, E.,Agrawal, S.,Wirchnianski, A.S.,Wilson, I.A.,Chandran, K.,Kitamura, S.
SuFEx-enabled high-throughput medicinal chemistry for developing potent tamoxifen analogs as Ebola virus entry inhibitors.
Front Immunol, 16:1533037-1533037, 2025

PubMed Abstract: Ebola virus (EBOV) causes severe hemorrhagic fever with a high mortality rate in humans. In acute infection, an abnormal immune response results in excessive inflammatory cytokines and uncontrolled systemic inflammation that can result in organ damage and multi-organ failure. While vaccines and monoclonal antibody therapies are available, there is an urgent need for effective small-molecule antivirals against EBOV. Here, we report on the optimization of tamoxifen, an EBOV-glycoprotein (GP) binder that inhibits viral entry, using our Sulfur-Fluoride Exchange (SuFEx) click chemistry-based high-throughput medicinal chemistry (HTMC) strategy. Using a "Direct-to-Biology" approach, we generated a focused library of 2,496 tamoxifen analogs overnight and screened them in a cell-based pseudo-EBOV infection assay. The HTMC workflow enabled the development of a potent EBOV entry inhibitor with submicromolar EC cellular antiviral activity and more than 50-fold improvement in binding affinity against EBOV-GP compared to the parent compound. Our findings underscore the use of SuFEx-enabled HTMC for rapidly generating and assessing potential therapeutic candidates against viral and immune-mediated diseases in a cell-based assay.

PubMed: 40356906
DOI: 10.3389/fimmu.2025.1533037

Experimental method

X-RAY DIFFRACTION (2.59 Å)