AI Article Synopsis
- The six-helix bundle (6-HB) is crucial for the fusion of viruses with host membranes, and current peptide inhibitors like Enfuvirtide face issues such as drug resistance and short effectiveness.
- This study focuses on creating new α-helical peptides as fusion inhibitors specifically targeting viruses like MERS-CoV and IAVs, using novel designs that are distinct from natural peptides.
- The research identified an effective artificial C-peptide, named 1SR, which prevents HIV-1 fusion by disrupting the 6-HB formation, offering a promising lead for future antiviral developments.
Article Abstract
Background: The six-helix bundle (6-HB) is a core structure formed during the membrane fusion process of viruses with the Class I envelope proteins. Peptide inhibitors, including the marketed Enfuvirtide, blocking the membrane fusion to exert inhibitory activity were designed based on the heptads repeat interactions in 6-HB. However, the drawbacks of Enfuvirtide, such as drug resistance and short half-life , have been confirmed in clinical applications. Therefore, novel design strategies are pivotal in the development of next-generation peptide-based fusion inhibitors.
Objective: The de novo design of α-helical peptides against MERS-CoV and IAVs has successfully expedited the development of fusion inhibitors. The reported sequences were completely nonhomologous with natural peptides, which can provide some inspirations for the antiviral design against other pathogenic viruses with class I fusion proteins. Here, we design a series of artificial C-peptides based on the similar mechanism of 6-HB formation and general rules of heptads repeat interaction.
Methods: The inhibitory activity of peptides against HIV-1 was assessed by HIV-1 Env-mediated cell-cell fusion assays. Interaction between artificial C-peptides and target peptides was evaluated by circular dichroism, polyacrylamide gel electrophoresis, size-exclusion chromatography, and sedimentation velocity analysis. Molecular docking studies were performed by using Schrödinger molecular modelling software.
Results: The best-performing artificial C-peptide, 1SR, was highly active against HIV-1 env-mediated cell-cell fusion. 1SR binds to the gp41 NHR region, assembling polymer to prevent endogenous 6-HB formation.
Conclusion: We have found an artificial C-lipopeptide lead compound with inhibitory activity against HIV-1. Also, this paper enriched both N- and C-teminal heptads repeat interaction rules in 6-HB and provided an effective idea for next-generation peptide-based fusion inhibitors against HIV-1.
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| http://dx.doi.org/10.2174/0109298665312274240530060233 | DOI Listing |
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Article Synopsis
- The six-helix bundle (6-HB) is crucial for the fusion of viruses with host membranes, and current peptide inhibitors like Enfuvirtide face issues such as drug resistance and short effectiveness.
- This study focuses on creating new α-helical peptides as fusion inhibitors specifically targeting viruses like MERS-CoV and IAVs, using novel designs that are distinct from natural peptides.
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