Minimalist Natural ORPphilin Macarangin B Delineates OSBP Biological Function,Journal of Medicinal Chemistry

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Minimalist Natural ORPphilin Macarangin B Delineates OSBP Biological Function
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-12-20 , DOI: 10.1021/acs.jmedchem.4c01705
Gwenaëlle Jézéquel, Zoé Grimanelli, Carole Guimard, Joëlle Bigay, Juliano Haddad, Jérôme Bignon, Cécile Apel, Vincent Steinmetz, Laurie Askenatzis, Hélène Levaïque, Clara Pradelli, Van Cuong Pham, Doan T. M. Huong, Marc Litaudon, Romain Gautier, Chaker El Kalamouni, Bruno Antonny, Sandy Desrat, Bruno Mesmin, Fanny Roussi

OSBP ligands from the ORPphilin family are chemically complex natural products with promising anticancer properties. Here, we describe macarangin B, a natural racemic flavonoid selective for OSBP, which stands out from other ORPphilins due to its structural simplicity and distinct biological activity. Using a bioinspired strategy, we synthesized both (R,R,R) and (S,S,S)-macarangin B enantiomers, enabling us to study their interaction with OSBP based on their unique optical properties. Experimental and computational analyzes revealed that (R,R,R)-macarangin B has the highest affinity for OSBP. Importantly, both enantiomers showed significantly decreased cytotoxicity compared to other ORPphilins, suggesting OSBP is not the primary target in ORPphilin-induced cell death. Yet, OSBP is an attractive antiviral target, as it is hijacked by many positive-strand RNA viruses. Remarkably, (R,R,R)-macarangin B significantly inhibited Zika virus replication in human cells, highlighting its potential as a lead compound for antiviral drug development.

更新日期：2024-12-20

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