ArticleProceedings of the National Academy of Sciences of the United States of America2010
Hydrocarbon double-stapling remedies the proteolytic instability of a lengthy peptide therapeutic.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 157 papers.
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Who cites it
157 citing papers in PubMed.
- Beyond the Active Site: First-In-Class Leishmania Infantum Trypanothione Reductase Dimerization Disruptors as Antileishmanial Leads.ChemMedChem · 2026Review
- Anticancer Peptides: Design Principles, Translational Bottlenecks, and Emerging Opportunities.Molecules (Basel, Switzerland) · 2026Review
- Mechanistic design of cell-penetrating disruptors for phospho-dependent TACC3-CHC interaction.Structure (London, England : 1993) · 2026Article
- Targeting "undruggable" cancer proteins: pharmacological challenges and emerging strategies.Translational cancer research · 2026Review
- Folded-state compatibility and unfolded-state constraint govern staple-based stabilization: guidelines from a coiled-coil model.RSC chemical biology · 2026Article
- A helical peptide antagonist of the human growth hormone receptor.Endocrinology · 2026Article
- Structure-Guided Design of Peptide Inhibitors Targeting Class I Viral Fusion Proteins.Pathogens (Basel, Switzerland) · 2025Review
- Structural insights into chemoresistance mutants of BCL-2 and their targeting by stapled BAD BH3 helices.Nature communications · 2025Article
- Unleashing the Antiviral Potential of Stapled Peptides: A New Frontier in Combating Human Neurotropic Viral Infections.Microbial biotechnology · 2025Review
- Modifying Antifungal Peptides as Safe Food Preservatives.Journal of agricultural and food chemistry · 2025Article
- From Concepts to Inhibitors: A Blueprint for Targeting Protein-Protein Interactions.Chemical reviews · 2025Review
- Structure-guided design and development of cyclic peptide allosteric activators of Polycomb Repressive Complex 2.bioRxiv : the preprint server for biology · 2025Article
- Review
- Direct inhibition of tumor hypoxia response with synthetic transcriptional repressors.Nature chemical biology · 2025Article
- Structure and Function of the SARS-CoV-2 6-HB Fusion Core and Peptide-based Fusion Inhibitors: A Review.Current medicinal chemistry · 2025Review
- Molecular Chimera in Cancer Drug Discovery: Beyond Antibody Therapy, Designing Grafted Stable Peptides Targeting Cancer.International journal of peptide research and therapeutics · 2025Review
- New insights into protein-protein interaction modulators in drug discovery and therapeutic advance.Signal transduction and targeted therapy · 2024Review
- Tackling Undruggable Targets with Designer Peptidomimetics and Synthetic Biologics.Chemical reviews · 2024Review
- The Role of Structural Flexibility in Hydrocarbon-Stapled Peptides Designed to Block Viral Infection via Human ACE2 Mimicry.Peptide science (Hoboken, N.J.) · 2024Article
- Targeted Degradation of Protein Kinase A via a Stapled Peptide PROTAC.ACS chemical biology · 2024Article
97 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors.
Funding
Abstract
The pharmacologic utility of lengthy peptides can be hindered by loss of bioactive structure and rapid proteolysis, which limits bioavailability. For example, enfuvirtide (Fuzeon, T20, DP178), a 36-amino acid peptide that inhibits human immunodeficiency virus type 1 (HIV-1) infection by effectively targeting the viral fusion apparatus, has been relegated to a salvage treatment option mostly due to poor in vivo stability and lack of oral bioavailability. To overcome the proteolytic shortcomings of long peptides as therapeutics, we examined the biophysical, biological, and pharmacologic impact of inserting all-hydrocarbon staples into an HIV-1 fusion inhibitor. We find that peptide double-stapling confers striking protease resistance that translates into markedly improved pharmacokinetic properties, including oral absorption. We determined that the hydrocarbon staples create a proteolytic shield by combining reinforcement of overall alpha-helical structure, which slows the kinetics of proteolysis, with complete blockade of peptide cleavage at constrained sites in the immediate vicinity of the staple. Importantly, double-stapling also optimizes the antiviral activity of HIV-1 fusion peptides and the antiproteolytic feature extends to other therapeutic peptide templates, such as the diabetes drug exenatide (Byetta). Thus, hydrocarbon double-stapling may unlock the therapeutic potential of natural bioactive polypeptides by transforming them into structurally fortified agents with enhanced bioavailability.
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