tetano
Editor, Senior Moderator
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[SUP] #[/SUP][SUP] 1 [/SUP], Eduardo Henrique Salviano Bezerra[SUP] #[/SUP][SUP] 1 [/SUP], Fernanda Aparecida Heleno Batista[SUP] #[/SUP][SUP] 1 [/SUP], Celisa Caldana Costa Tonoli[SUP] 1 [/SUP], Adriana Santos Soprano[SUP] 1 [/SUP], Jacqueline Farinha Shimizu[SUP] 1 [/SUP], Alice Nagai[SUP] 1 [/SUP], Jaqueline Cristina da Silva[SUP] 1 [/SUP], Helder Veras Ribeiro Filho[SUP] 1 [/SUP], Jéssica do Nascimento Faria[SUP] 1 [/SUP], Marcos Guilherme da Cunha[SUP] 1 [/SUP], Ana Carolina Mattos Zeri[SUP] 2 [/SUP], Andrey Fabricio Ziem Nascimento[SUP] 2 [/SUP], José Luiz Proenca-Modena[SUP] 3 4 [/SUP], Marcio Chaim Bajgelman[SUP] 1 [/SUP], Silvana Aparecida Rocco[SUP] 1 [/SUP], Paulo Sérgio Lopes-de-Oliveira[SUP] 1 [/SUP], Artur Torres Cordeiro[SUP] 1 [/SUP], Marjorie Bruder[SUP] 1 [/SUP], Rafael Elias Marques[SUP] 1 [/SUP], Mauricio Luis Sforça[SUP] 1 [/SUP], Kleber Gomes Franchini[SUP] 1 [/SUP], Celso Eduardo Benedetti[SUP] 1 [/SUP], Ana Carolina Migliorini Figueira[SUP] 5 [/SUP], Daniela Barretto Barbosa Trivella[SUP] 6 [/SUP]
Affiliations
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, [SUP]1[/SUP]H-STD and [SUP]15[/SUP]N-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.
. 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[SUP] #[/SUP][SUP] 1 [/SUP], Eduardo Henrique Salviano Bezerra[SUP] #[/SUP][SUP] 1 [/SUP], Fernanda Aparecida Heleno Batista[SUP] #[/SUP][SUP] 1 [/SUP], Celisa Caldana Costa Tonoli[SUP] 1 [/SUP], Adriana Santos Soprano[SUP] 1 [/SUP], Jacqueline Farinha Shimizu[SUP] 1 [/SUP], Alice Nagai[SUP] 1 [/SUP], Jaqueline Cristina da Silva[SUP] 1 [/SUP], Helder Veras Ribeiro Filho[SUP] 1 [/SUP], Jéssica do Nascimento Faria[SUP] 1 [/SUP], Marcos Guilherme da Cunha[SUP] 1 [/SUP], Ana Carolina Mattos Zeri[SUP] 2 [/SUP], Andrey Fabricio Ziem Nascimento[SUP] 2 [/SUP], José Luiz Proenca-Modena[SUP] 3 4 [/SUP], Marcio Chaim Bajgelman[SUP] 1 [/SUP], Silvana Aparecida Rocco[SUP] 1 [/SUP], Paulo Sérgio Lopes-de-Oliveira[SUP] 1 [/SUP], Artur Torres Cordeiro[SUP] 1 [/SUP], Marjorie Bruder[SUP] 1 [/SUP], Rafael Elias Marques[SUP] 1 [/SUP], Mauricio Luis Sforça[SUP] 1 [/SUP], Kleber Gomes Franchini[SUP] 1 [/SUP], Celso Eduardo Benedetti[SUP] 1 [/SUP], Ana Carolina Migliorini Figueira[SUP] 5 [/SUP], Daniela Barretto Barbosa Trivella[SUP] 6 [/SUP]
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, [SUP]1[/SUP]H-STD and [SUP]15[/SUP]N-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.