SuFEx-enabled high-throughput medicinal chemistry for developing potent tamoxifen analogs as Ebola virus entry inhibitors
Year: 2025
Type: article
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 50 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.
Source: Frontiers in Immunology
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
Awards: G1229526393, G1286251239, G1804828992, G1831385526, G2300450775, G2371548206, G262532246, G303061748, G315621713, G3488436650, G3629260272, G4235786860, G4280418065, Console and probe upgrade for 600 MHz NMR, G4581610328, G495301720, G498139845, G5097437870, G5570207115, G6550344761, G7283024673, A Synchroton Radiation Structural Biology Resource, G8382000481, G8925327636, G9000069621, G9000108980, Expanding the chemical probe development paradigm toward underexplored targets, Cancer Center Support Grant, G911061179, G969889393
OpenAlex ID: W4409866031