Journal of medicinal chemistry · 2024
Minimalist Natural ORPphilin Macarangin B Delineates OSBP Biological Function.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Jézéquel Gwenaëlle, Grimanelli Zoé, Guimard Carole, Bigay Joëlle, Haddad Juliano, Bignon Jérôme, Apel Cécile, Steinmetz Vincent, Askenatzis Laurie, Levaïque Hélène, Pradelli Clara, Pham Van Cuong, Huong Doan T M, Litaudon Marc, Gautier Romain, El Kalamouni Chaker, Antonny Bruno, Desrat Sandy, Mesmin Bruno, Roussi Fanny
Аннотация
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.