Targeting protein-protein interaction interfaces with antiviral N protein inhibitor in SARS-CoV-2.
Biophys J
; 123(4): 478-488, 2024 Feb 20.
Article
em En
| MEDLINE
| ID: mdl-38234090
ABSTRACT
Coronaviruses not only pose significant global public health threats but also cause extensive damage to livestock-based industries. Previous studies have shown that 5-benzyloxygramine (P3) targets the Middle East respiratory syndrome coronavirus (MERS-CoV) nucleocapsid (N) protein N-terminal domain (N-NTD), inducing non-native protein-protein interactions (PPIs) that impair N protein function. Moreover, P3 exhibits broad-spectrum antiviral activity against CoVs. The sequence similarity of N proteins is relatively low among CoVs, further exhibiting notable variations in the hydrophobic residue responsible for non-native PPIs in the N-NTD. Therefore, to ascertain the mechanism by which P3 demonstrates broad-spectrum anti-CoV activity, we determined the crystal structure of the SARS-CoV-2 N-NTDP3 complex. We found that P3 was positioned in the dimeric N-NTD via hydrophobic contacts. Compared with the interfaces in MERS-CoV N-NTD, P3 had a reversed orientation in SARS-CoV-2 N-NTD. The Phe residue in the MERS-CoV N-NTDP3 complex stabilized both P3 moieties. However, in the SARS-CoV-2 N-NTDP3 complex, the Ile residue formed only one interaction with the P3 benzene ring. Moreover, the pocket in the SARS-CoV-2 N-NTDP3 complex was more hydrophobic, favoring the insertion of the P3 benzene ring into the complex. Nevertheless, hydrophobic interactions remained the primary stabilizing force in both complexes. These findings suggested that despite the differences in the sequence, P3 can accommodate a hydrophobic pocket in N-NTD to mediate a non-native PPI, enabling its effectiveness against various CoVs.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Coronavírus da Síndrome Respiratória do Oriente Médio
/
COVID-19
Limite:
Humans
Idioma:
En
Revista:
Biophys J
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Taiwan