Macrocyclic peptides Peptide cyclization is a fundamental strategy employed to enhance the metabolic stability, bioavailability, and receptor binding affinity of peptidesThe Pseudoproline Approach to Peptide Cyclization. By forming a cyclic structure, linear peptides can be transformed into molecules with improved pharmacological properties and bioactivity.作者：KA Jolliffe·2018·被引用次数：14—In general,placing a pseudoproline close to the centre of the linear peptideis the most effective strategy to increase cyclization yield, but including a ... This process involves various "peptide cyclization strategies" that link different parts of the peptide chain, such as the head, tail, or side chains, to create a closed loop.作者：D Buchanan·2025·被引用次数：12—Cyclization, a critical step in their synthesis,enhances metabolic stability, bioavailability, and receptor binding affinity. Advances in synthetic ... Understanding these diverse methodologies is crucial for peptide engineering and drug development, as the choice of strategy significantly impacts the resulting cyclic peptide's characteristics.
The landscape of peptide cyclization is rich with diverse methodologies, each offering unique advantages for creating cyclic peptides and peptidomimetics. These strategies aim to efficiently form new bonds within a peptide chain, thereby altering its conformation and properties.
Head-to-Tail Cyclization: This is one of the most prevalent strategies, involving the formation of a bond between the N-terminus (head) and the C-terminus (tail) of a peptide.Biocompatible strategies for peptide macrocyclisation This "backbone cyclization" is a key technique in stabilizing peptide conformations for drug design.
Side-Chain Cyclization: Strategies that involve linking amino acid side chains are also widely used作者：N Ghosh·2024—A simple, highly efficient, and green procedure forside-chain to side-chain in situ peptide cyclizationis established here at the physiological condition.. This can include:
* Side-Chain to Side-Chain: Forming a bond between two amino acid side chains.
* Terminus-to-Side-Chain: Linking either the N- or C-terminus to an amino acid side chainA novel computational method for head-to-tail peptide ....
Disulfide Bond Formation: A classic method involves the formation of disulfide bonds between cysteine residues, creating a stable cyclic structure. This is particularly effective for peptides containing two cysteine amino acids.
Macrolactamization: This strategy involves forming an amide bond between an amine and a carboxylic acid group within the peptide chain, leading to the creation of a lactam ring. This can occur between termini or side chains作者：TR Oppewal·2022·被引用次数：59—We report anefficient two-step strategyto access MPs via the programmed modification of a unique cysteine residue and an N-terminal amine..
Thiol Alkylation: This method typically involves using a chemical linker, such as one containing methyl bromide groups, to react with thiol groups of cysteine residues, forming a stable cyclic structure. Other thiol-based strategies can involve the radical addition of a thiol group to an alkene.
Beyond the established methods, ongoing research continuously expands the toolkit for peptide cyclization, introducing more efficient, selective, and biocompatible approaches.
Enzymatic and Biocatalytic Methods: The use of enzymes or biocatalysis offers a greener and often more selective alternative to purely chemical synthesis. These methods can achieve peptide cyclization under milder conditions.作者：Y Zhang·2019·被引用次数：145—This OPAcyclizationmethod extends the toolbox for integrating post-cyclizationmodification and bioconjugation intopeptide cyclizationwith all-in-one manner ...
Peptide Tag Approaches: In some cases, protein tags can be employed to facilitate or direct the cyclization processChemical cyclization is a critical step that converts a linear peptide into a cyclic form. Common strategies include:Head-to-tail/Backbone cyclization: For ....
Stapled Peptides: While not strictly cyclization in the traditional sense, "stapled" peptides involve introducing hydrocarbon staples to stabilize helical secondary structures. This approach shares the goal of enhancing peptide stability and bioactivity.
Pseudoproline Incorporation: Introducing pseudoproline residues at specific positions within a linear peptide, often near the center, can significantly increase cyclization yields by influencing peptide conformationIsothiocyanate-mediated cyclization of phage-displayed ....
Imine-Induced Ring-Closing Strategies: These advanced methods can overcome high energy barriers associated with cyclization, enabling the formation of complex cyclic structures.
The primary motivation behind employing "peptide cyclization strategies" lies in the significant advantages they confer upon peptides:
* Enhanced Metabolic Stability: Cyclic peptides are generally more resistant to enzymatic degradation compared to their linear counterparts, leading to longer half-lives in biological systems.2019年5月30日—Cyclic peptide synthesis strategies. The cyclization step is perhaps the most important step in the synthesis of cyclic peptides. There are ...
* Improved Bioavailability: The conformational rigidity and altered physicochemical properties can lead to better absorption and distribution.
* Increased Receptor Binding Affinity and Selectivity: The constrained conformation can pre-organize the peptide for optimal interaction with its target receptor, often leading to higher affinity and specificity.
* Mimicry of Secondary Structures: Cyclization can stabilize specific peptide secondary structures, such as beta-turns or helices, which are crucial for biological activity.
These enhanced properties make cyclic peptides highly attractive for therapeutic applications, serving as potential drug candidates for a wide range of diseases. Their ability to target protein-protein interactions and bind to challenging protein targets further broadens their therapeutic potential.
Peptide cyclization strategies are indispensable tools in modern peptide chemistry and drug discovery. From classic head-to-tail linkages to more sophisticated side-chain modifications and biocatalytic approaches, these methods provide a versatile platform for engineering peptides with improved stability, bioavailability, and targeted activity. As research progresses, we can anticipate even more innovative strategies emerging, further unlocking the potential of cyclic peptides in medicine and beyond作者：BS Nunez·2021—The aim of this study is to explore an alternative strategy that utilizesbiocatalysisas a method of achieving successful peptide cyclization..
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