Minimalist\nNatural ORPphilin Macarangin B Delineates\nOSBP Biological Function

OSBP ligands from the ORPphilin family\nare chemically\ncomplex natural\nproducts with promising anticancer properties. Here, we describe macarangin\nB, a natural racemic flavonoid selective for OSBP, which stands out\nfrom other ORPphilins due to its structural simplicity and distinct\nbiological activity. Using a bioinspired strategy, we synthesized\nboth (<i>R</i>,<i>R</i>,<i>R</i>) and\n(<i>S</i>,<i>S</i>,<i>S</i>)-macarangin\nB enantiomers, enabling us to study their interaction with OSBP based\non their unique optical properties. Experimental and computational\nanalyzes revealed that (<i>R</i>,<i>R</i>,<i>R</i>)-macarangin B has the highest affinity for OSBP. Importantly,\nboth enantiomers showed significantly decreased cytotoxicity compared\nto other ORPphilins, suggesting OSBP is not the primary target in\nORPphilin-induced cell death. Yet, OSBP is an attractive antiviral\ntarget, as it is hijacked by many positive-strand RNA viruses. Remarkably,\n(<i>R</i>,<i>R</i>,<i>R</i>)-macarangin\nB significantly inhibited Zika virus replication in human cells, highlighting\nits potential as a lead compound for antiviral drug development.