De novo design of isopeptide bond-tethered triple-stranded coiled coils with exceptional resistance to unfolding and proteolysis: implication for developing antiviral therapeutics. Issue 11 (14th August 2015)

• Record Type: Journal Article
• Authors: Wang, Chao; Lai, Wenqing; Yu, Fei; Zhang, Tianhong; Lu, Lu; Jiang, Xifeng; Zhang, Zhenqing; Xu, Xiaoyu; Bai, Yu; Jiang, Shibo; Liu, Keliang
• Is Part Of: Chemical science. Volume 6:Issue 11(2015:Nov.)
• Page Start: 6505
• Page End: 6509
• Publication Date: 2015-08-14
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c5sc02220g
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : Isopeptide bridge-tethered ultra-stable coiled-coil trimers have been de novo designed as structure-directing auxiliaries to guide HIV-1 gp41 NHR-peptide trimerization. Abstract : Isopeptide bond-tethered triple-stranded coiled coils of HIV-1 gp41 N-terminal heptad repeat (NHR) peptides have been designed with de novo auxiliaries to guide site-directed trimerized cross-linking. The presence of isopeptide bridges in the rationally designed trimerization motifs provides extraordinary stability to withstand thermal and chemical denaturation. As a result, these ultra-stable and well-folded trimeric coiled coils direct and yield proteolysis-resistant and remarkably potent N-peptide chimeric trimers with HIV-1 fusion inhibitory activities in the low nanomolar range, much more effective than the corresponding unstructured N-peptide monomers and reaching the potency of clinically used T20 peptide (enfuvirtide). Thus, these isopeptide bond-crosslinked de novo coiled coils may also be used as attractive scaffolds for isolating NHR-trimers in other class I enveloped viruses for therapeutic intervention. Furthermore, this isopeptide bridge-tethering strategy could be extendable to the construction of ultra-stable proteins interfering with certain biological processes.