Entry Inhibitors of SARS-CoV-2 Targeting the Transmembrane Domain of the Spike Protein.

ABSTRACT: Despite current vaccines and therapeutics targeting SARS-CoV-2, the causative agent of the COVID-19 pandemic, cases remain high causing a burden on health care systems. Spike-protein mediated membrane fusion of SARS-CoV-2 is a critical step in viral entry. Herein, we describe entry inhibitors identified by first screening a library of about 160 compounds and then analogue synthesis. Specifically, compound 261 was found to inhibit SARS-CoV-2 infection in a tissue model with IC₅₀ of 0.3 µM. Using NMR, we found that 261 interacts with key residues in the aromatic-rich region of the spike protein directly next to the transmembrane domain. Molecular dynamic simulations of the 261 binding pocket in the spike protein was also mapped to the transmembrane domain, con

SUBMITTER: Lyles KV 

PROVIDER: S-EPMC12300635 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature