Antiviral drug design based on structural insights into the N-terminal domain and C-terminal domain of the SARS-CoV-2 nucleocapsid protein

Xiaodong Luan; Xinming Li; Yufan Li; Gengchen Su; Wanchao Yin; Yi Jiang; Ning Xu; Feng Wang; Wang Cheng; Ye Jin; Leike Zhang; H Eric Xu; Yi Xue; Shuyang Zhang

doi:10.1016/j.scib.2022.10.021

Antiviral drug design based on structural insights into the N-terminal domain and C-terminal domain of the SARS-CoV-2 nucleocapsid protein

Sci Bull (Beijing). 2022 Nov 30;67(22):2327-2335. doi: 10.1016/j.scib.2022.10.021. Epub 2022 Oct 27.

Authors

Xiaodong Luan^{1

2

3}, Xinming Li^{3

4

5}, Yufan Li^{1

2}, Gengchen Su^{1

2}, Wanchao Yin⁶, Yi Jiang⁶, Ning Xu^{4

5}, Feng Wang⁷, Wang Cheng⁷, Ye Jin², Leike Zhang⁸, H Eric Xu^{6

9}, Yi Xue^{3

4

5}, Shuyang Zhang^{2

1

3}

Affiliations

¹ School of Medicine, Tsinghua University, Beijing 100084, China.
² Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
³ Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.
⁴ School of Life Science, Tsinghua University, Beijing 100084, China.
⁵ Beijing Advanced Innovation Center for Structural Biology, Beijing 100084, China.
⁶ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁷ WuxiBiortus Biosciences Co., Ltd., Jiangyin 214437, China.
⁸ State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China.
⁹ University of Chinese Academy of Sciences, Beijing 100049, China.

Abstract

Nucleocapsid (N) protein plays crucial roles in the life cycle of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including the formation of ribonucleoprotein (RNP) complex with the viral RNA. Here we reported the crystal structures of the N-terminal domain (NTD) and C-terminal domain (CTD) of the N protein and an NTD-RNA complex. Our structures reveal a unique tetramer organization of NTD and identify a distinct RNA binding mode in the NTD-RNA complex, which could contribute to the formation of the RNP complex. We also screened small molecule inhibitors of N-NTD and N-CTD and discovered that ceftriaxone sodium, an antibiotic, can block the binding of RNA to NTD and inhibit the formation of the RNP complex. These results together could facilitate the further research of antiviral drug design targeting N protein.

Keywords: Ceftriaxone sodium; N-terminal domain; Nucleocapsid protein; SARS-CoV-2.