Minimalist Natural ORPphilin Macarangin B Delineates OSBP Biological Function

• Published in: Journal of medicinal chemistry 2025-01, Vol.68 (1), p.196-211
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological Products - chemical synthesis; Biological Products - chemistry; Biological Products - pharmacology; Chemical Sciences; Flavonoids - chemistry; Flavonoids - pharmacology; Humans; Molecular Docking Simulation; Stereoisomerism; Structure-Activity Relationship; Virus Replication - drug effects; Zika Virus - drug effects
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c01705

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.