Design and concise synthesis of halicyclamine-inspired bis-macrocycles targeting DedA membrane proteins.

DedA membrane proteins promote the formation of double-membrane vesicles serving as replication platforms for RNA viruses, including SARS-CoV-2. Inspired by the only known inhibitor, halicyclamine A, we developed a concise biomimetic synthesis of halicyclamine-inspired macrocycles, identifying bis-macrocycles that suppress SARS-CoV-2 replication, while exhibiting DedA-associated activity in a bacterial overexpression assay.