2. Academic Validation
  3. Structural basis of DNA aptamer A58 targeting the N-terminal domain of sarbecoviruses nucleocapsid protein

Structural basis of DNA aptamer A58 targeting the N-terminal domain of sarbecoviruses nucleocapsid protein

  • J Biol Chem. 2026 Mar;302(3):111233. doi: 10.1016/j.jbc.2026.111233.
Xiaoxue Chen 1,  Suhua He 2,  Shaojie Xue 3,  Yuhang Luo 4,  Zhizhong Lu 5,  Shuang Zhu 5,  Zhichao Miao 6,  Shoudeng Chen 7,  Lin Huang 8
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Department of Pharmacy, Sun-Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2 Molecular Imaging Center, the Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China; Guangzhou National Laboratory, Guangzhou, China.
  • 3 Molecular Imaging Center, the Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.
  • 4 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 5 School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China.
  • 6 GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou National Laboratory, Guangzhou Medical University, Guangzhou International Bio Island, Guangzhou, China; Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China. Electronic address: [email protected].
  • 7 Molecular Imaging Center, the Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China; Central Laboratory, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China. Electronic address: [email protected].
  • 8 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. Electronic address: [email protected].
PMID: 41651417 DOI: 10.1016/j.jbc.2026.111233
Abstract

In the post-pandemic era, the persistent threat of coronaviruses demands broad-spectrum Antiviral therapeutic strategies. The SARS-CoV-2 nucleocapsid protein (N protein), an essential factor for genome packaging and immune modulation, poses a promising Antiviral target. Here, we determined the crystal structure of the DNA aptamer A58-T10 in complex with the N-terminal domain of the N protein (N-NTD). A58-T10 binds to the N-NTD via a unique three-tiered stem-loop that interacts with the nucleic acid-binding site of N-NTD through extensive hydrogen bonding and stacking. Structural analysis reveals that A58 contains two stem-loops with octanucleotide motifs (5'-11ACCGGATT19-3' and 5'-26ATCGGATT33-3') that specifically recognize N-NTD. Functionally, A58 inhibits N-NTD's binding to viral RNA, disrupting N protein-host cell interactions involved in immune responses. Notably, A58 exhibits broad-spectrum binding activity against N proteins from SARS-CoV-2 variants and related sarbecoviruses. These findings elucidate the specific interaction mechanism between A58 and N-NTD, highlighting its potential as an anti-sarbecovirus agent.

Keywords

DNA aptamer; crystal structure; inhibitor; nucleocapsid protein; sarbecoviruses.

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