Minimalist Natural ORPphilin Macarangin B Delineates OSBP Biological Function

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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.
Funding Information
  • Agence Nationale de la Recherche (ANR-10-LABX-25-01, ANR-11-LABX-0028-01, ANR-21-CE13-0021-01, CDE-2019-002288, IRE 2019-083)
  • European Research Council (856404)
  • Institut National de la Sant? et de la Recherche M?dicale
  • Universit? Paris-Saclay
  • Universit? C?te d?Azur
  • Centre National de la Recherche Scientifique
  • Conseil R?gional de La R?union (RE0028005)
  • Grand ?quipement National De Calcul Intensif (A0150714646, AD010714001)
  • SATT PARIS-SACLAY (CM2017-0045)

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