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Author Notes:

Correspondence and requests for materials should be addressed to S.J. (email: shibojiang@fudan.edu.cn) or K.L. (email: keliangliu55@126.com).

K.L. and S.J. conceived and supervised the project.

C.W. and X.L. performed design and synthesis.

F.Y., L.L., X.J., X.X., H.W., and L.Y. performed biological evaluation.

W.L., T.Z., and Z.Z. performed metabolic stability assessment.

C.W., K.L. and S.J. wrote the paper.

We thank Ms. Xiaoxia Yu at Institute of Biophysics, Chinese Academy of Sciences, and Dr. Baohua Zheng and Prof. Luhua Lai at the College of Chemistry and Molecular Engineering, Peking University for technical support for sedimentation equilibrium centrifugation.

The authors declare no competing financial interests.

Subjects:

Research Funding:

This research was supported, in part, by grants from the National Natural Science Foundation of China (81373266, 81573266, 81501735 and 81361120378).

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • FUSION INHIBITORS
  • ENTRY INHIBITORS
  • COILED-COIL
  • PEPTIDE
  • DESIGN
  • STABILITY
  • TARGET
  • BUNDLE
  • REGION
  • POTENT
  • HIV infections
  • Structure-based drug design

Site-specific Isopeptide Bridge Tethering of Chimeric gp41 N-terminal Heptad Repeat Helical Trimers for the Treatment of HIV-1 Infection

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Journal Title:

Scientific Reports

Volume:

Volume 6

Publisher:

, Pages 32161-32161

Type of Work:

Article | Final Publisher PDF

Abstract:

Peptides derived from the N-terminal heptad repeat (NHR) of HIV-1 gp41 can be potent inhibitors against viral entry when presented in a nonaggregating trimeric coiled-coil conformation via the introduction of exogenous trimerization motifs and intermolecular disulfide bonds. We recently discovered that crosslinking isopeptide bridges within the de novo helical trimers added exceptional resistance to unfolding. Herein, we attempted to optimize (CCIZN17)3, a representative disulfide bond-stabilized chimeric NHR-trimer, by incorporating site-specific interhelical isopeptide bonds as the redox-sensitive disulfide surrogate. In this process, we systematically examined the effect of isopeptide bond position and molecular sizes of auxiliary trimeric coiled-coil motif and NHR fragments on the antiviral potency of these NHR-trimers. Pleasingly, (IZ14N24N)3 possessed promising inhibitory activity against HIV-1 infection and markedly increased proteolytic stability relative to its disulfide-tethered counterpart, suggesting good potential for further development as an effective antiviral agent for treatment of HIV-1 infection.

Copyright information:

© 2016, The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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