ArticleThe Journal of biological chemistry2012
The M-T hook structure is critical for design of HIV-1 fusion inhibitors.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed.
- Structure-Guided Design of Peptide Inhibitors Targeting Class I Viral Fusion Proteins.Pathogens (Basel, Switzerland) · 2025Review
- Heptad repeat 1-derived N peptide inhibitors improve broad-spectrum anti-HIV-1 activity.Current research in microbial sciences · 2025Article
- Article
- Broad-spectrum anti-HIV activity and high drug resistance barrier of lipopeptide HIV fusion inhibitor LP-19.Frontiers in immunology · 2023Article
- In Vitro Selection and Characterization of HIV-1 Variants with Increased Resistance to LP-40, Enfuvirtide-Based Lipopeptide Inhibitor.International journal of molecular sciences · 2022Article
- Article
- Systematic Evaluation of Fluorination as Modification for Peptide-Based Fusion Inhibitors against HIV-1 Infection.Chembiochem : a European journal of chemical biology · 2021Article
- HIV-1 Entry and Membrane Fusion Inhibitors.Viruses · 2021Review
- Preparation and evaluation of amphipathic lipopeptide-loaded PLGA microspheres as sustained-release system for AIDS prevention.Engineering in life sciences · 2020Article
- The Tryptophan-Rich Motif of HIV-1 gp41 Can Interact with the N-Terminal Deep Pocket Site: New Insights into the Structure and Function of gp41 and Its Inhibitors.Journal of virology · 2019Article
- Mutations of Glu560 within HIV-1 Envelope Glycoprotein N-terminal heptad repeat region contribute to resistance to peptide inhibitors of virus entry.Retrovirology · 2019Article
- A Membrane-Anchored Short-Peptide Fusion Inhibitor Fully Protects Target Cells from Infections of Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus.Journal of virology · 2019Article
- Article
- Monotherapy with a low-dose lipopeptide HIV fusion inhibitor maintains long-term viral suppression in rhesus macaques.PLoS pathogens · 2019Article
- Sulfono-γ-AA modified peptides that inhibit HIV-1 fusion.Organic & biomolecular chemistry · 2018Article
- Structural and Functional Characterization of Membrane Fusion Inhibitors with Extremely Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus.Journal of virology · 2018Article
- Molecular mechanism of HIV-1 resistance to sifuvirtide, a clinical trial-approved membrane fusion inhibitor.The Journal of biological chemistry · 2018Article
- Design of Novel HIV-1/2 Fusion Inhibitors with High Therapeutic Efficacy in Rhesus Monkey Models.Journal of virology · 2018Article
- Mechanism of HIV-1 Resistance to an Electronically Constrained α-Helical Peptide Membrane Fusion Inhibitor.Journal of virology · 2018Article
- Efficient Fusion at Neutral pH by Human Immunodeficiency Virus gp41 Trimers Containing the Fusion Peptide and Transmembrane Domains.Biochemistry · 2018Article
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9 authors.
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Abstract
CP621-652 is a potent HIV-1 fusion inhibitor peptide derived from the C-terminal heptad repeat of gp41. We recently identified that its N-terminal residues Met-626 and Thr-627 adopt a unique hook-like structure (termed M-T hook) thus stabilizing the interaction of the inhibitor with the deep pocket on the N-terminal heptad repeat. In this study, we further demonstrated that the M-T hook structure is a key determinant of CP621-652 in terms of its thermostability and anti-HIV activity. To directly define the structure and function of the M-T hook, we generated the peptide MT-C34 by incorporating Met-626 and Thr-627 into the N terminus of the C-terminal heptad repeat-derived peptide C34. The high resolution crystal structure (1.9 Å) of MT-C34 complexed by an N-terminal heptad repeat-derived peptide reveals that the M-T hook conformation is well preserved at the N-terminal extreme of the inhibitor. Strikingly, addition of two hook residues could dramatically enhance the binding affinity and thermostability of 6-helix bundle core. Compared with C34, MT-C34 exhibited significantly increased activity to inhibit HIV-1 envelope-mediated cell fusion (6.6-fold), virus entry (4.5-fold), and replication (6-fold). Mechanistically, MT-C34 had a 10.5-fold higher increase than C34 in blocking 6-helix bundle formation. We further showed that MT-C34 possessed higher potency against T20 (Enfuvirtide, Fuzeon)-resistant HIV-1 variants. Therefore, this study provides convincing data for our proposed concept that the M-T hook structure is critical for designing HIV-1 fusion inhibitors.
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