Zoé Grimanelli

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.

Hijacking host cell lipid homeostatic pathways is a hallmark of infection by RNA-positive viruses. A key protein exploited by these viruses to facilitate replication is the lipid exchanger Oxysterol-binding protein (OSBP), making it an attractive target for antiviral strategies. However, the known OSBP ligands are poorly selective, and those of natural origin, referred to as ORPphilins, exhibit pronounced cytotoxicity. Here, we describe macarangin B, a new racemic flavonoid isolated from a Vietnamese bushy tree. This compound features a rare hydroxy-hexahydroxanthene moiety that confers the ability to bind OSBP. Using a bio-inspired method, we performed the total synthesis of both (R, R, R) and (S, S, S) enantiomers, allowing us to examine their distinct interaction with OSBP, based on their unique optical properties. Together, experimental and computational approaches indicate that the (R, R, R) enantiomer has the highest affinity for OSBP. We show that replication of the health-threatening Flavivirus Zika virus in infected human cells is strongly reduced by treatment with (R, R, R)-macarangin B, which selectively targets OSBP. Importantly, both enantiomers exhibit significantly decreased cytotoxicity when compared to the previously characterized ORPphilins, positioning (R, R, R)-macarangin B as a promising lead for the development of a novel family of antivirals.