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- Title
Identification of the SARS-unique domain of SARS-CoV-2 as an antiviral target.
- Authors
Qin, Bo; Li, Ziheng; Tang, Kaiming; Wang, Tongyun; Xie, Yubin; Aumonier, Sylvain; Wang, Meitian; Yuan, Shuofeng; Cui, Sheng
- Abstract
SARS-CoV-2 nsp3 is essential for viral replication and host responses. The SARS-unique domain (SUD) of nsp3 exerts its function through binding to viral and host proteins and RNAs. Herein, we show that SARS-CoV-2 SUD is highly flexible in solution. The intramolecular disulfide bond of SARS-CoV SUD is absent in SARS-CoV-2 SUD. Incorporating this bond in SARS-CoV-2 SUD allowed crystal structure determination to 1.35 Å resolution. However, introducing this bond in SARS-CoV-2 genome was lethal for the virus. Using biolayer interferometry, we screened compounds directly binding to SARS-CoV-2 SUD and identified theaflavin 3,3'-digallate (TF3) as a potent binder, Kd 2.8 µM. TF3 disrupted the SUD-guanine quadruplex interactions and exhibited anti-SARS-CoV-2 activity in Vero E6-TMPRSS2 cells with an EC50 of 5.9 µM and CC50 of 98.5 µM. In this work, we provide evidence that SARS-CoV-2 SUD harbors druggable sites for antiviral development. The SARS-unique domain (SUD) of SARS-CoV-2 plays important roles in virus life cycle. Here the authors determine the crystal structure of SARS-CoV-2 SUD and perform a compound screen, which identify theaflavin 3,3'-digallate as a potent SUD binder that exhibits anti-SARS-CoV-2 activity.
- Subjects
ANTIVIRAL agents; SARS-CoV-2; LIFE cycles (Biology); VIRAL proteins; QUADRUPLEX nucleic acids; VIRAL replication; CRYSTAL structure; GUANINE
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-39709-6