Minimalist Natural ORPphilin Macarangin B Delineates OSBP Biological Function
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 (<i>R</i>,<i>R</i>,<i>R</i>) and (<i>S</i>,<i>S</i>,<i>S</i>)-macarangin B enantiomers, enabling us to study their interaction with OSBP based on their unique optical properties. Experimental and computational analyzes revealed that (<i>R</i>,<i>R</i>,<i>R</i>)-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, (<i>R</i>,<i>R</i>,<i>R</i>)-macarangin B significantly inhibited Zika virus replication in human cells, highlighting its potential as a lead compound for antiviral drug development.
Authors
- Joëlle Bigay (ORCID: https://orcid.org/0000-0002-7487-3416)
- Van Cuong Pham (ORCID: https://orcid.org/0000-0003-1317-6382)
- Jérôme Bignon (ORCID: https://orcid.org/0000-0002-6294-9671)
- Bruno Antonny (ORCID: https://orcid.org/0000-0002-9166-8668)
- Bruno Mesmin (ORCID: https://orcid.org/0000-0002-5437-3246)
- Cécile Apel (ORCID: https://orcid.org/0000-0003-3785-9620)
- Marc Litaudon (ORCID: https://orcid.org/0000-0002-0877-8234)
- Romain Gautier (ORCID: https://orcid.org/0000-0001-6678-132X)
- Laurie Askenatzis (ORCID: https://orcid.org/0000-0003-4122-2139)
- Gwenaëlle Jézéquel (ORCID: https://orcid.org/0000-0001-8945-8680)
- Sandy Desrat (ORCID: https://orcid.org/0000-0002-6544-9242)
- Chaker El Kalamouni (ORCID: https://orcid.org/0000-0003-4673-6614)
- Fanny Roussi (ORCID: https://orcid.org/0000-0002-5941-9901)
- Hélène Levaïque
- Juliano G. Haddad (ORCID: https://orcid.org/0000-0001-5035-0162)
- Zoé Grimanelli (ORCID: https://orcid.org/0009-0009-7495-285X)
- Carole Guimard
- Clara Pradelli
- Đoàn Thị Mai Hương (ORCID: https://orcid.org/0000-0003-3252-870X)
- Vincent Steinmetz (ORCID: https://orcid.org/0000-0003-4394-2471)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Institut de Chimie des Substances Naturelles (FR)
- Inserm (FR)
- Université Côte d'Azur (FR)
- Université Paris-Saclay (FR)
- Processus Infectieux en Milieu Insulaire Tropical (RE)
- Institut de Pharmacologie Moléculaire et Cellulaire (FR)
- Institut de Recherche pour le Développement (FR)
- Vietnam Academy of Science and Technology (VN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-20
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01705
- Citations
- 7
- Primary Topic
- Signaling Pathways in Disease
- Type
- article
- Field-Weighted Citation Impact
- 1.64
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Centre National de la Recherche Scientifique
- Université Paris-Saclay
- Conseil Régional de La Réunion
- Grand Équipement National De Calcul Intensif
- Université Côte d’Azur
- Société d'Accélération du Transfert de Technologies
- European Research Council