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 (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.