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HTRF-based identification of small molecules targeting SARS-CoV-2 E protein interaction with ZO-1 PDZ2
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HTRF-based identification of small molecules targeting SARS-CoV-2 E protein interaction with ZO-1 PDZ2
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Journal Article
HTRF-based identification of small molecules targeting SARS-CoV-2 E protein interaction with ZO-1 PDZ2
2025
Overview
The SARS-CoV-2 E protein through its C-terminal PDZ-binding motif (PBM) interacts with several host PDZ-containing proteins, including Zonula occludens-1 (ZO-1) protein via its PDZ2 domain, thereby contributing to viral pathogenesis. Targeting this interaction represents a potential therapeutic strategy. In this study, we determined the X-ray structure of the E PBM peptide in complex with the ZO-1 PDZ2 domain at 1.7 Å resolution. The structure revealed a domain-swapped dimer conformation of ZO-1 PDZ2, with the E PBM peptide conventionally bound within the PDZ domain’s canonical binding groove, exhibiting key interactions characteristic of type II PBM/PDZ interactions. To identify potential inhibitors of the E PBM/ZO-1 PDZ2 interaction, we performed a Homogeneous Time-Resolved Fluorescence (HTRF) screening using a protein-protein interaction-focused library of 1000 compounds. This led to the identification of 36 hits that disrupted this interaction. Subsequent cytotoxicity and dose-response assays narrowed the selection to 14 promising compounds. Docking simulations showed that some compounds bind within or near the PBM-binding pocket, supporting a competitive mechanism of interaction inhibition, while others bind at a central interface between the two PDZ monomers, suggesting an inhibition of dimerization, which in turn prevents PBM binding. Thus, the E PBM/ZO-1 PDZ2 interaction can be inhibited through both direct and indirect mechanisms. Finally, antiviral assays using a NanoLuciferase-expressing recombinant SARS-CoV-2 demonstrated that one compound, C19, significantly reduced viral replication, highlighting its potential as a candidate for further therapeutic development.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 631/154
/ 631/45
/ 631/535
/ 631/57
/ Antiviral Agents - chemistry
/ Antiviral Agents - pharmacology
/ Antiviral compound screening
/ Coronavirus Envelope Proteins - chemistry
/ Coronavirus Envelope Proteins - metabolism
/ COVID-19
/ Humanities and Social Sciences
/ Humans
/ Ligands
/ Mutation
/ Peptides
/ Protein Binding - drug effects
/ Proteins
/ Science
/ Severe acute respiratory syndrome coronavirus 2
/ Small Molecule Libraries - chemistry
/ Small Molecule Libraries - pharmacology
/ ZO-1
