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Minimalist Natural ORPphilin Macarangin B Delineates OSBP Biological Function
Gwenaëlle Jézéquel1, Zoé Grimanelli2, Carole Guimard1
1CNRS, Institut de Chimie des Substances Naturelles, Université Paris-Saclay, Gif-sur-Yvette 91198, France.
Journal of Medicinal Chemistry
|December 20, 2024
Summary
Macarangin B, a simple flavonoid, selectively binds OSBP. The (R,R,R) enantiomer inhibits Zika virus replication, showing potential for antiviral drug development.
Area of Science:
- Natural Product Chemistry
- Virology
- Medicinal Chemistry
Background:
- ORPphilin family members are complex natural products with anticancer potential.
- Oxysterol-binding protein (OSBP) is crucial for viral replication and an antiviral target.
Purpose of the Study:
- To synthesize and characterize macarangin B enantiomers.
- To investigate the interaction of macarangin B enantiomers with OSBP.
- To evaluate the antiviral activity of macarangin B enantiomers.
Main Methods:
- Bioinspired synthesis of (R,R,R)- and (S,S,S)-macarangin B enantiomers.
- Experimental and computational analyses of OSBP-macarangin B interactions.
- Zika virus replication assays in human cells.
Main Results:
- (R,R,R)-macarangin B exhibits higher affinity for OSBP than its enantiomer.
- Macarangin B enantiomers show reduced cytotoxicity compared to other ORPphilins.
- (R,R,R)-macarangin B significantly inhibits Zika virus replication.
Conclusions:
- OSBP is likely not the primary target for ORPphilin-induced cytotoxicity.
- (R,R,R)-macarangin B is a potent inhibitor of Zika virus replication.
- Macarangin B represents a promising lead compound for antiviral drug discovery targeting OSBP.
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