Bio-inspired synthesis and profiling of a potent antiviral flavonol targeting the lipid exchanger OSBP

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.