Journal
CHEMICAL SCIENCE
Volume 6, Issue 11, Pages 6505-6509Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c5sc02220g
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Funding
- National Science Foundation of China [81373266, 81173098, 81361120378]
- National Science and Technology Major Project of China [2012ZX09301003]
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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.
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