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Sci Rep
. 2022 Nov 2;12(1):18500.
doi: 10.1038/s41598-022-22576-4.
Discovery and structural characterization of chicoric acid as a SARS-CoV-2 nucleocapsid protein ligand and RNA binding disruptor
Gustavo Fernando Mercaldi # 1 , Eduardo Henrique Salviano Bezerra # 1 , Fernanda Aparecida Heleno Batista # 1 , Celisa Caldana Costa Tonoli 1 , Adriana Santos Soprano 1 , Jacqueline Farinha Shimizu 1 , Alice Nagai 1 , Jaqueline Cristina da Silva 1 , Helder Veras Ribeiro Filho 1 , Jéssica do Nascimento Faria 1 , Marcos Guilherme da Cunha 1 , Ana Carolina Mattos Zeri 2 , Andrey Fabricio Ziem Nascimento 2 , José Luiz Proenca-Modena 3 4 , Marcio Chaim Bajgelman 1 , Silvana Aparecida Rocco 1 , Paulo Sérgio Lopes-de-Oliveira 1 , Artur Torres Cordeiro 1 , Marjorie Bruder 1 , Rafael Elias Marques 1 , Mauricio Luis Sforça 1 , Kleber Gomes Franchini 1 , Celso Eduardo Benedetti 1 , Ana Carolina Migliorini Figueira 5 , Daniela Barretto Barbosa Trivella 6
Affiliations
- PMID: 36323732
- DOI: 10.1038/s41598-022-22576-4
Abstract
The nucleocapsid (N) protein plays critical roles in coronavirus genome transcription and packaging, representing a key target for the development of novel antivirals, and for which structural information on ligand binding is scarce. We used a novel fluorescence polarization assay to identify small molecules that disrupt the binding of the N protein to a target RNA derived from the SARS-CoV-2 genome packaging signal. Several phenolic compounds, including L-chicoric acid (CA), were identified as high-affinity N-protein ligands. The binding of CA to the N protein was confirmed by isothermal titration calorimetry, 1H-STD and 15N-HSQC NMR, and by the crystal structure of CA bound to the N protein C-terminal domain (CTD), further revealing a new modulatory site in the SARS-CoV-2 N protein. Moreover, CA reduced SARS-CoV-2 replication in cell cultures. These data thus open venues for the development of new antivirals targeting the N protein, an essential and yet underexplored coronavirus target.