Hydrocarbon stapledpeptides: principles, practice, and progress Hydrocarbon stapled peptides represent a significant advancement in peptide engineering, offering enhanced stability, improved cellular permeability, and increased bioactivity compared to their natural counterparts. By introducing a synthetic hydrocarbon "staple" that locks the peptide into a desired alpha-helical conformation, these modified peptides overcome key limitations of traditional peptide-based therapeutics, making them valuable tools for biomedical research and promising candidates for prototype therapeutics. This innovative approach leverages the inherent versatility of peptides while imbuing them with the robust characteristics often associated with small molecules.
The fundamental principle behind hydrocarbon stapled peptides involves the covalent linkage of two amino acid residues within the peptide chain.作者：JM Song·2019·被引用次数：17—Hydrocarbon stapled (HCS) peptidesare a class of cross-linked α-helix mimetics. The technology relies on the use of α,α′-disubstituted ... This linkage, typically achieved through an alpha, alpha'-disubstituted amino acid, creates a hydrocarbon bridge. This "staple" effectively constrains the peptide's conformation, most commonly stabilizing it in an alpha-helical structure. This enhanced helicity is crucial, as many biologically active peptides exert their function through helical motifs.
The incorporation of a hydrocarbon staple confers several critical advantages, significantly expanding the therapeutic potential of peptides:
* Increased Protease Resistance: Natural peptides are often rapidly degraded by proteases in vivo, limiting their therapeutic efficacy and necessitating frequent administration. The hydrocarbon staple provides a shield, rendering the peptide significantly more resistant to proteolytic breakdown. This enhanced stability translates to longer half-lives and improved pharmacokinetic profiles.
* Enhanced Cellular Permeability: A major hurdle for peptide therapeutics is their inability to efficiently cross cell membranes and reach intracellular targets. Hydrocarbon stapled peptides have demonstrated a markedly enhanced ability to penetrate cellular membranes. This improved cell permeability opens up new avenues for targeting intracellular proteins and pathways that were previously inaccessible to traditional peptides.
* Stabilized Alpha-Helical Conformation: The staple locks the peptide into its bioactive alpha-helical structure. This pre-organization can lead to increased binding affinity to target molecules and a more potent biological response. By maintaining a consistent and active conformation, these engineered peptides offer greater predictability in their interaction with biological systems.
* Improved Binding Affinity: The constrained helical structure often results in a more precise fit with target proteins, leading to increased binding affinity and specificity作者：B Chen·2023·被引用次数：10—Usually,stapled peptides are obtained by a hydrocarbon stapling technique... hydrocarbon peptide stapling provided more potential for peptide therapeutics.. This can translate to higher potency and reduced off-target effects.
The unique properties of hydrocarbon stapled peptides have led to their exploration across a wide range of biomedical applications. They serve as powerful molecular probes for dissecting complex protein-protein interactions and are being developed as potential therapeutics for various diseases.
* Targeting Protein-Protein Interactions (PPIs): Many disease processes are driven by aberrant protein-protein interactions.Hydrocarbon-Stapled Peptides: Principles, Practice, and ... Peptides that mimic natural interaction interfaces can disrupt these processes. Hydrocarbon stapled peptides, with their enhanced stability and ability to mimic natural helices, are particularly well-suited for inhibiting PPIs that involve helical motifs. Examples include targeting oncogenic pathways or disrupting viral entry mechanisms.The modified hydrocarbon-stapled peptide ishelical, relatively protease resistant, cell-permeableand binds with increased binding affinity to its target.
* Antimicrobial Peptides (AMPs): The development of new antimicrobial agents is a critical need作者：GL Verdine·2012·被引用次数：93—Stapled peptideshave proven effective in combining the versatile surface recognition properties of protein therapeutics with the ability of small molecules to .... Hydrocarbon stapling has been applied to cationic antimicrobial peptides (CAPs) to enhance their stability and efficacyHydrocarbon Stapled & Constrained Peptides. These modified AMPs can exhibit increased antimicrobial activity while maintaining or even reducing hemolytic activity, a common side effect of some natural AMPs.
* Antitumor Agents: Research has shown that stapled peptides can exhibit improved antitumor activity.Facile Synthesis of Hydrocarbon-Stapled Peptides By stabilizing helical structures that interact with cancer-related targets, these engineered peptides offer a promising strategy for cancer therapy.
* Modulators of Biological Pathways: Hydrocarbon stapled peptides are being designed to modulate various biological pathways, including those involved in autophagy, membrane fusion, and other cellular processes.Hydrocarbon Stapled Peptides: To Advance Antimicrobial ... Their ability to penetrate cells and interact with specific targets makes them versatile tools for modulating complex biological systems.2025年10月1日—Hydrocarbon stapled peptides, including single, multiple, and stitched stapling strategies, improve α-helical conformation, enhance resistance ...
The synthesis of hydrocarbon stapled peptides typically involves the incorporation of specific amino acids, such as alpha,alpha'-disubstituted alanine derivatives bearing alkenyl side chainsStapled Peptides. These side chains undergo ring-closing metathesis (RCM) to form the hydrocarbon staple.Hydrocarbon-stapled peptides: principles, practice ... - PubMed Advances in synthetic methodologies, including automated synthesis, have made the preparation of these complex molecules more accessible作者：Z Wang·2024·被引用次数：10—We present StaPep, a Python-based toolkit forgenerating3D structures and calculating 21 features for hydrocarbon-stapled peptides..
Designing effective stapled peptides requires careful consideration of the target protein's structure and the desired conformational changes. Factors such as the length and position of the staple, the geometry of the olefin used in stapling, and the overall amphipathic nature of the peptide play critical roles in determining the resulting structure, stability, and biological activity.作者：GL Verdine·2012·被引用次数：93—Stapled peptideshave proven effective in combining the versatile surface recognition properties of protein therapeutics with the ability of small molecules to ... Tools like StaPep have been developed to aid in the generation of 3D structures and feature calculations for hydrocarbon-stapled peptides, facilitating rational design.
While all-hydrocarbon stapled peptides offer significant advantages, researchers are also exploring other stapling strategies, such as triazole stapling, which may offer benefits in terms of synthesis cost and catalyst toxicity.Additionally, some hydrocarbon-stapled peptideshave been shown to have greater cell permeability and in vivo activitythan their unstapled analogues, which has ...
The field of hydrocarbon stapled peptides continues to evolve rapidlyThe role of olefin geometry in the activity of hydrocarbon .... Ongoing research focuses on refining synthesis techniques, exploring novel stapling strategies, and expanding their application to a broader range of therapeutic targets. The ability to combine the exquisite specificity of peptides with the pharmacokinetic advantages of small molecules positions hydrocarbon stapled peptides as a powerful platform for the next generation of therapeutics and research tools.All-hydrocarbon stapled peptides as Synthetic Cell- ... Their potential to address previously intractable biological targets underscores their importance in modern drug discovery and development.
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