An effective strategy for recapitulating N-terminal heptad repeat trimers in enveloped virus surface glycoproteins for therapeutic applications† †Electronic supplementary information (ESI) available: General materials, methods, and the details. See DOI: 10.1039/c5sc04046a

We report an efficient strategy to recapitulate NHR α-helical trimers in the HIV-1 membrane fusion protein as promising antiviral therapeutics. Sequestering peptides derived from the N-terminal heptad repeat (NHR) of class I viral fusion proteins into a non-aggregating trimeric coiled-coil conformation remains a major challenge. Here, we implemented a synthetic strategy to stabilize NHR-helical trimers, with the human immunodeficiency virus type 1 (HIV-1) gp41 fusion protein as the initial focus. A set of trimeric scaffolds was realized in a synthetic gp41 NHR-derived peptide sequence by relying on the tractability of coiled-coil structures and an additional isopeptide bridge-tethering strategy. Among them, (N36M) 3 folded as a highly stable helical trimer and exhibited promising inhibitory activity against HIV-1 infection, exceptional resistance to proteolysis, and effective native ligand-binding capability. We anticipate that the trimeric coiled-coil recapitulation methodology described herein may have broader applicability to yield NHR trimers of other class I enveloped viruses and to prepare helical tertiary structure mimetics of certain natural protein–protein interactions for biomedical applications.