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<p>The SARS-CoV-2 nucleocapsid protein (N), essential for viral RNA packaging, comprises a structured RNA-binding domain, NTD(44–180), flanked by intrinsically disordered regions, IDR1 (1–43) and IDR2 (181–248). This extended, positively charged RNA-binding surface makes it an attractive target for synthetic ligands able to interfere with its function. In this study, peptide ligands were explored as synthetically accessible alternatives for modulating N interactions. After confirming the ability of a reference peptide (P0) in engaging IDRs in the interaction, we shifted our attention to key properties that modulate the interaction with the central domain NTD(44–180). Two new peptides (P1 and P2) were designed with identical amino acid compositions but distinct sequence arrangements. In each one a para-fluorinated phenylalanine residue was incorporated to introduce an aromatic component useful to mimic RNA bases and enable <sup>19</sup>F NMR detection. Molecular dynamics simulations, circular dichroism, and NMR spectroscopy were combined to characterize the structural, dynamic and binding properties of P1 and P2. Both peptides involve the RNA-binding groove of the N protein (NTD(44–180)). While P1 demonstrated higher α-helical propensity and favorable electrostatic interactions, P2 displayed stronger interactions through enhanced conformational adaptability. <sup>19</sup>F NMR experiments confirmed complex formation also from the ligand perspective. These findings support a modular peptide design strategy for targeting multidomain proteins.</p>

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Peptide ligands to explore interactions with intrinsically disordered multidomain proteins: the case of SARS-CoV-2 nucleocapsid protein

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月18日

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  • A. S. Tino,
  • M. Quagliata,
  • M. Schiavina,
  • L. Attanasio,
  • B. P. O. Santos,
  • L. Pacini,
  • A. M. Papini,
  • R. Pierattelli,
  • I. C. Felli

摘要

The SARS-CoV-2 nucleocapsid protein (N), essential for viral RNA packaging, comprises a structured RNA-binding domain, NTD(44–180), flanked by intrinsically disordered regions, IDR1 (1–43) and IDR2 (181–248). This extended, positively charged RNA-binding surface makes it an attractive target for synthetic ligands able to interfere with its function. In this study, peptide ligands were explored as synthetically accessible alternatives for modulating N interactions. After confirming the ability of a reference peptide (P0) in engaging IDRs in the interaction, we shifted our attention to key properties that modulate the interaction with the central domain NTD(44–180). Two new peptides (P1 and P2) were designed with identical amino acid compositions but distinct sequence arrangements. In each one a para-fluorinated phenylalanine residue was incorporated to introduce an aromatic component useful to mimic RNA bases and enable 19F NMR detection. Molecular dynamics simulations, circular dichroism, and NMR spectroscopy were combined to characterize the structural, dynamic and binding properties of P1 and P2. Both peptides involve the RNA-binding groove of the N protein (NTD(44–180)). While P1 demonstrated higher α-helical propensity and favorable electrostatic interactions, P2 displayed stronger interactions through enhanced conformational adaptability. 19F NMR experiments confirmed complex formation also from the ligand perspective. These findings support a modular peptide design strategy for targeting multidomain proteins.