Heptad repeat 1-derived N peptide inhibitors improve broad-spectrum anti-HIV-1 activity
Background: HIV-1 N-peptide inhibitor (NPI) derived from N-terminal heptad-repeat region (HR1) of gp41 can target C-terminal heptad-repeat region (HR2) or the HR1 to interfere with the formation of endogenous six-helix bundle (6HB). However, the NPI is less active than the C-peptide inhibitor. In th...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-01-01
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| Series: | Current Research in Microbial Sciences |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666517425000264 |
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| Summary: | Background: HIV-1 N-peptide inhibitor (NPI) derived from N-terminal heptad-repeat region (HR1) of gp41 can target C-terminal heptad-repeat region (HR2) or the HR1 to interfere with the formation of endogenous six-helix bundle (6HB). However, the NPI is less active than the C-peptide inhibitor. In this study, we reported three HR1-derived NPIs designed by adding fusion peptide proximal region (FPPR) of gp41 or a trimeric motif MTQ into the N36 peptide and then evaluated their anti-HIV-1 activities. Methods: Molecular modeling was performed using Swiss Model. The inhibitory activity of NPIs on HIV-1 was assessed by Env-pseudovirus infection assays and cell-cell fusion assays. Interaction between NPIs and HR2 peptides was evaluated by circular dichroism and Native PAGE. Results: The three newly designed NPIs, FPPR-N36, MTQ-N36, and MTQ-FPPR-N36, exhibited higher anti-HIV-1 activity than N36. The stability of the coiled-coil core formed by three designed NPIs or the 6HB formed by C34 and these NPIs were significantly higher than those of corresponding monomer N36 or isoleucine zipper-engineered trimeric N36 (IZN36). The 50 % inhibitory concentrations (IC50) of MTQ-N36 against HIV-1 infection were at a nanomolar level, lower than those of other tested NPIs. The FPPR-N36 could also inhibit infection of HIV-1 strains that were resistant to N36 and IZN36. Conclusions: The three newly designed NPIs had inhibitory activity against HIV-1 infection. Among them, MTQ-N36 exhibited a higher potential to inhibit HIV-1 entry than other peptides, and FPPR-N36 might be a promising candidate NPI for suppressing HIV-1 strains that are resistant to conventional NPIs. |
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| ISSN: | 2666-5174 |