Abstract
HIV-1 fusion with the target cell is initiated by the insertion of the gp41 fusion peptide (FP) into the target cell membrane and the interaction between the gp41 N- and C-terminal heptad repeats (NHR and CHR), followed by the formation of the six-helix bundle (6-HB) fusion core. Therefore, both FP and NHR are important targets for HIV-1 fusion inhibitors. Here, we designed and synthesized a dual-target peptidic HIV-1 fusion inhibitor, 4HR-LBD-VIRIP, in which 4HR-LBD is able to bind to the gp41 NHR domain, while VIRIP is able to interact with gp41 FP. We found that 4HR-LBD-VIRIP is about tenfold more potent than 4HR-LBD and VIRIP in inhibiting HIV-1IIIB infection and HIV-1 envelope glycoprotein (Env)-mediated cell–cell fusion, suggesting that this dual-target HIV-1 fusion inhibitor possesses a strong synergistic antiviral effect. A biophysical analysis indicates that 4HR-LBD-VIRIP can interact with N70 peptide that contains the gp41 NHR and FP domains and binds with lipid membrane. This study provides a new approach for designing novel viral fusion inhibitors against HIV and other enveloped viruses with class I membrane fusion proteins.
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This work was supported by Grants from the National Natural Science Foundation of China (81202390, 81373266, 81361120378, 81501735, and 81573266).
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The authors declare that they have no conflicts of interest.
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This article does not contain any studies with human participants or animals performed by any of the authors.
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Handling Editor: J. Bode.
X. Jiang and Q. Jia contributed equally to this work.
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Jiang, X., Jia, Q., Lu, L. et al. A novel bispecific peptide HIV-1 fusion inhibitor targeting the N-terminal heptad repeat and fusion peptide domains in gp41. Amino Acids 48, 2867–2873 (2016). https://doi.org/10.1007/s00726-016-2325-x
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DOI: https://doi.org/10.1007/s00726-016-2325-x