No abstract

No abstract

The nucleoprotein (NP) of Ebola virus (EBOV) and Marburg virus (MARV) is an essential component of the viral ribonucleoprotein complex and significantly impacts replication and transcription of the viral RNA genome. Although NP is regarded as a promising antiviral druggable target, no chemical ligands have been reported to interact with EBOV NP or MARV NP. We identified two compounds from a traditional Chinese medicine Gancao (licorice root) that can bind both NPs by combining affinity mass spectrometry and metabolomics approaches. These two ligands, 18β-glycyrrhetinic acid and licochalcone A, were verified by defined compound mixture screens and further characterized with individual ligand binding assays. Accompanying biophysical analyses demonstrate that binding of 18β-glycyrrhetinic acid to EBOV NP significantly reduces protein thermal stability, induces formation of large NP oligomers, and disrupts the critical association of viral ssRNA with NP complexes whereas the compound showed no such activity on MARV NP. Our study has revealed the substantial potential of new analytical techniques in ligand discovery from natural herb resources. In addition, identification of a chemical ligand that influences the oligomeric state and RNA-binding function of EBOV NP sheds new light on antiviral drug development.

Carbon monoxide (CO) as an emerging treatment holds great promise for inducing the apoptosis of cancer cells. Here coordination assembled strategy is first reported for synthesis of Cu(II)‐flavone coordination polymer (NCu‐FleCP) CO nanoprodrug that is stable in normal physiological conditions, and yet readily reduces to small size prodrug complex and releases CO on demand under glutathione (GSH) and near infrared (NIR) light. Specifically, after uptaking by cancer cells, local GSH attacked coordination bond within NCu‐FleCP, resulting in the release of Cu(I) and free Fle. The CC bond of Fle is cleavage under NIR light to release CO for gas therapy, and Cu(I) reacts with local H2O2 through Fenton like reaction to generate hydroxyl radicals (•OH) for chemodynamic therapy. Detailed in vitro and in vivo experiments demonstrate that the CO prodrug system in generating a sufficient quantity of CO and •OH offers remarkable destructive effects against cancer cells without causing toxicity to surrounding normal tissues. The study provides a solid foundation to develop smart coordination polymer CO prodrugs with on‐demand CO release, enhanced permeability and retention effect, and biodegradability for multimodal synergistic therapy.