Minimalist Natural ORPphilin Macarangin B Delineates OSBP Biological Function

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry 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

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Abstract

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.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.