Targeting protein-protein interaction interfaces with antiviral N protein inhibitor in SARS-CoV-2

Hong, Jhen-Yi; Lin, Shih-Chao; Kehn-Hall, Kylene; Zhang, Kai-Min; Luo, Shun-Yuan; Wu, Hung-Yi; Chang, Sui-Yuan; Hou, Ming-Hon

doi:10.1016/j.bpj.2024.01.013

Cited by 2 publications

(1 citation statement)

References 51 publications

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“…In addition, three hydrogen bonds between 5-benzyloxygramine and the NTD dimer can be observed. These interactions are the driving forces for the formation of stabilized NTD dimers according to previous literature. ,, However, both the hydrophobic interactions and hydrogen bonding were diminished at the binding interface of 5-benzyloxygramine with SARS-CoV NTD, implying that a much weaker binding affinity between 5-benzyloxygramine and SARS-CoV NTD. These theoretical calculations are well consistent with the experimental results obtained by plasmonic imaging.…”

Section: Resultssupporting

confidence: 66%

Plasmonic Imaging of Multivalent NTD–Nucleic Acid Interactions for Broad-Spectrum Antiviral Drug Analysis

Chen,

Sun,

Liu

et al. 2024

Anal. Chem.

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The discovery and identification of broad-spectrum antiviral drugs are of great significance for blocking the spread of pathogenic viruses and corresponding variants of concern. Herein, we proposed a plasmonic imaging-based strategy for assessing the efficacy of potential broad-spectrum antiviral drugs targeting the N-terminal domain of a nucleocapsid protein (NTD) and nucleic acid (NA) interactions. With NTD and NA conjugated gold nanoparticles as core and satellite nanoprobes, respectively, we found that the multivalent binding interactions could drive the formation of core− satellite nanostructures with enhanced scattering brightness due to the plasmonic coupling effect. The core−satellite assembly can be suppressed in the presence of antiviral drugs targeting the NTD−NA interactions, allowing the drug efficacy analysis by detecting the dose-dependent changes in the scattering brightness by plasmonic imaging. By quantifying the changes in the scattering brightness of plasmonic nanoprobes, we uncovered that the constructed multivalent weak interactions displayed a 500-fold enhancement in affinity as compared with the monovalent NTD−NA interactions. We demonstrated the plasmonic imaging-based strategy for evaluating the efficacy of a potential broad-spectrum drug, PJ34, that can target the NTD−NA interactions, with the IC 50 as 24.35 and 14.64 μM for SARS-CoV-2 and SARS-CoV, respectively. Moreover, we discovered that ceftazidime holds the potential as a candidate drug to inhibit the NTD−NA interactions with an IC 50 of 22.08 μM from molecular docking and plasmonic imaging-based drug analysis. Finally, we validated that the potential antiviral drug, 5-benzyloxygramine, which can induce the abnormal dimerization of nucleocapsid proteins, is effective for SARS-CoV-2, but not effective against SARS-CoV. All these demonstrations indicated that the plasmonic imaging-based strategy is robust and can be used as a powerful strategy for the discovery and identification of broad-spectrum drugs targeting the evolutionarily conserved viral proteins.

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Section: Resultssupporting

confidence: 66%