An effective strategy for recapitulating N-terminal heptad repeat trimers in enveloped virus surface glycoproteins for therapeutic applications. Issue 3 (7th January 2016)

• Record Type: Journal Article
• Authors: Lai, Wenqing; Wang, Chao; Yu, Fei; Lu, Lu; Wang, Qian; Jiang, Xifeng; Xu, Xiaoyu; Zhang, Tianhong; Wu, Shengming; Zheng, Xi; Zhang, Zhenqing; Dong, Fangting; Jiang, Shibo; Liu, Keliang
• Is Part Of: Chemical science. Volume 7:Issue 3(2016:Mar.)
• Page Start: 2145
• Page End: 2150
• Publication Date: 2016-01-07
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c5sc04046a
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : We report an efficient strategy to recapitulate NHR α-helical trimers in the HIV-1 membrane fusion protein as promising antiviral therapeutics. Abstract : 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.