Macrocyclization strategies for cyclic peptides and peptidomimetics Peptide cyclization is a critical modification technique that transforms linear peptides into cyclic structures, significantly enhancing their stability, bioavailability, and therapeutic potential. By imposing a specific three-dimensional conformation, cyclization can improve target binding affinity and reduce susceptibility to enzymatic degradation. Understanding the diverse peptide cyclization methods available is essential for researchers aiming to design novel peptides for drug discovery and other applications. This guide explores the leading strategies, from established chemical approaches to emerging enzymatic and tag-based methodologies, providing insights into their strengths and limitations, and highlighting the advancements shaping this dynamic field.
Chemical synthesis offers a broad spectrum of methods for inducing peptide cyclization, allowing for precise control over the resulting cyclic structureMethods of Peptide Cyclization ·Head-to-Tail Cyclization· Side-Chain-to-Side-Chain Cyclization · Other Cyclization Methods.. These approaches often involve forming a new covalent bond, either between the termini of the peptide chain or through its side chains.
* Head-to-Tail Cyclization: This is a fundamental peptide cyclization strategy where the N-terminus of the peptide is linked to the C-terminus, forming a continuous ring.12小时前—Cyclicpeptidesexhibit advantages in binding protein targets with high affinity and competency in inhibiting protein-protein interactions. This can be achieved through various chemical ligation techniques. One common approach involves the formation of a peptide bond between the terminal amino and carboxyl groups.
* Side-Chain Cyclization: This method utilizes reactive groups present on the amino acid side chains to create a cyclic structureChemoselective Peptide Cyclization and Bicyclization Directly .... Examples include:
* Lactamization: This involves forming an amide bond between a side-chain amino group and a side-chain carboxyl group, or between a side-chain functional group and a terminus. Three methods for peptide cyclization via lactamization are often employed, utilizing either solution-phase or solid-phase peptide synthesis followed by cyclization.
* Disulfide Cyclization: This strategy leverages the thiol groups of cysteine residues to form a disulfide bond, creating a cyclic peptide. This method is particularly useful for stabilizing peptide structures.作者：AD Foster·2015·被引用次数：60—The majority of biologically produced cyclic peptide libraries are formed usingphage/phagemid display,or by split-intein cyclisation of peptides and proteins ...
* Thiol Alkylation: Similar to disulfide cyclization, this method uses a thiol group, often from a cysteine residue, to react with an alkylating agent, forming a thioether linkage.
* Thioether Cyclization: This involves forming a stable carbon-sulfur bond, often between a cysteine residue and an appropriately functionalized side chain or terminus作者：HC Hayes·2021·被引用次数：133—Cyclisation can be achieved by methods includingchemical, enzyme and protein tag approaches. Each has strengths and limitations..
Recent advances in chemical macrocyclization strategies for cyclic peptides have focused on developing highly efficient and selective methodsApproaches for peptide and protein cyclisation - PMC. For instance, rapid peptide cyclization techniques inspired by biosynthetic processes are emerging, offering unprecedented speed and yieldAn improved method for the solution cyclization of peptides .... Strategies employing "traceless turn-inducers" also provide a versatile route to facilitate specific cyclization events.
Enzymatic methods harness the specificity of biological catalysts to achieve peptide cyclization. These approaches can offer milder reaction conditions and high selectivity, making them attractive alternatives to purely chemical synthesis.Cyclic Peptides: Promising Scaffolds for Biopharmaceuticals
* Enzyme-Mediated Cyclization: Certain enzymes can catalyze the formation of amide bonds, facilitating head-to-tail cyclization of peptides or side-chain linkages.The Pseudoproline Approach to Peptide Cyclization This approach is particularly relevant for synthesizing complex cyclic peptides that are challenging to produce chemically.
* Protein Tag Approaches: While less common for small peptides, protein tags can sometimes be engineered to facilitate cyclization. This often involves specific ligation chemistries that can be triggered by enzymatic activity or chemical reagents.
The field of peptide cyclization is continually evolving with new peptide cyclization methodologies being developed to address limitations of existing techniques and expand the scope of accessible cyclic peptide structures作者：P Fang·2024·被引用次数：49—In this tutorial review,diverse state-of-the-art macrocyclization methodologiesand techniques for peptides and peptidomimetics are surveyed and discussed..
* Solid-Phase Peptide Synthesis (SPPS) and Solution-Phase Cyclization: A common workflow involves synthesizing a linear peptide precursor using SPPS, followed by cleavage from the resin and subsequent cyclization in solution. This solution-phase macrocyclization following solid-phase peptide synthesis allows for better control over reaction conditions during the critical cyclization step.
* Chemoselective Cyclization: This focuses on using highly specific chemical reactions that target particular functional groups, minimizing unwanted side reactions and improving yields.Cyclization· Stapling · N-Methylation of the Peptide Backbone · Phosphorylation · Myristylation/Palmitylation · Glycosylation · Isoprenylation (Farnesylation/ ... Chemoselective peptide cyclization and bicyclization methods are crucial for constructing complex cyclic peptide librariesThree Methods for Peptide Cyclization Via Lactamization.
* High-Concentration Cyclization: Developing methods that allow for efficient cyclization at high peptide concentrations is crucial for industrial scalability and reducing reaction volumes.作者：X Jia·2023·被引用次数：20—The most common strategy to achieve macrocyclisation is byligation of the termini of the peptide chain through a peptide bond. Chemically this ... Techniques that prevent aggregation and oligomerization are key in this area.Recent advances in peptide macrocyclization strategies
* Peptidomimetics: Beyond natural amino acids, cyclization strategies are also applied to peptidomimetics, molecules that mimic the structure and function of peptides but possess modified backbones or side chains. This broadens the chemical space for therapeutic development.
Peptide cyclization is a powerful tool for enhancing the pharmacological properties of peptides, leading to more stable, potent, and selective therapeutics. The diverse array of peptide cyclization methods, ranging from classical chemical ligations to modern enzymatic and chemoselective approaches, provides researchers with a rich toolkit. As research continues to uncover novel peptide cyclization strategies and refine existing ones, the potential for cyclic peptides in medicine and beyond will undoubtedly continue to grow, offering innovative solutions for challenging biological targets and unmet clinical needs.作者：AD Foster·2015·被引用次数：60—The majority of biologically produced cyclic peptide libraries are formed usingphage/phagemid display,or by split-intein cyclisation of peptides and proteins ...
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