Contemporary strategies forpeptide macrocyclization Peptide macrocyclization is a critical synthetic strategy that transforms linear peptides into cyclic structures, offering significant advantages in stability, affinity, and therapeutic potential.Contemporary strategies for peptide macrocyclization These macrocyclic peptides are increasingly recognized for their ability to combine the benefits of small-molecule drugs with the specificity of biological therapeutics, driving innovation in drug discovery and materials science.作者：F Smith·2024·被引用次数：12—Synthetic methods that enable the macrocyclisation ofpeptidesfacilitate the development of more effective therapeutic and diagnostic tools. Recent advances in methodologies have expanded the toolkit for achieving efficient and diverse peptide macrocyclization, addressing challenges in creating conformationally stable and functionally potent cyclic peptides.
At its core, peptide macrocyclization involves forming a covalent bond that closes a linear peptide chain into a ring. This cyclization can occur between various points of the peptide backbone, such as the N-terminus and C-terminus (head-to-tail cyclization), or through side-chain linkages, or a combination of backbone and side-chain connections. The resulting macrocyclic peptides often exhibit enhanced resistance to enzymatic degradation, improved pharmacokinetic profiles, and precisely defined three-dimensional structures that can lead to higher binding affinity and selectivity for their biological targetsEnzyme-Catalyzed Macrocyclization of Long Unprotected .... This structural rigidity is a key factor in their utility, allowing for more predictable interactions with proteins and other biomolecules.
The field of peptide macrocyclization has seen continuous development in its synthetic approaches. Traditional methods often rely on lactam formation, where an amine group reacts with a carboxylic acid to form an amide bond, closing the ring. However, contemporary strategies leverage a broader range of chemical reactions, including:
* Head-to-Tail Cyclization: This common approach involves forming an amide bond between the terminal amino group of one end of the peptide and the terminal carboxyl group of the other. This is often achieved using standard peptide coupling reagents.作者：MB Coppock·被引用次数：10—Peptide MacrocyclizationThrough Palladium-Catalyzed Late-Stage C-H Activation. Chuangxu Cai, Shu Liu, Huan Wang. Pages 31-42. Three Methods for the Solution ...
* Side-Chain Cyclization: Linking amino acid side chains, such as through disulfide bonds between cysteine residues or amide bonds formed from amino and carboxyl groups on side chains, offers another route to macrocyclic structures.
* Click Chemistry: Reactions like the copper-catalyzed azide-alkyne cycloaddition (CuAAC) have become popular due to their high efficiency, selectivity, and mild reaction conditions, allowing for the facile formation of triazole linkages within the peptide ring.
* Transition Metal Catalysis: Palladium-catalyzed reactions, including C-H activation, have emerged as powerful tools for late-stage functionalization and macrocyclization, enabling the formation of complex cyclic peptides.
* Photoredox Catalysis: This method offers new avenues for decarboxylative macrocyclization, providing alternative pathways under mild conditions.
* Enzymatic Approaches: Enzymes, such as endoproteases or glutathione S-transferases (GSTs), are being harnessed for peptide macrocyclization, offering high specificity and the ability to cyclize longer, unprotected peptides. These biocatalytic methods are particularly appealing for their potential sustainability and reduced side-product formation.
* Reversible Covalent Chemistry: Strategies employing reversible covalent bonds can facilitate templated synthesis of macrocyclic peptides, guiding the cyclization process.
The choice of strategy often depends on the specific peptide sequence, the desired ring size, the required stereochemistry, and the presence of sensitive functional groups.作者：C Bechtler·2021·被引用次数：196—This review provides an updated summary of the availablemacrocyclizationchemistries, such as traditional lactam formation, azide–alkyne cycloadditions, ring- ... Advances in solid-phase synthesis and combinatorial chemistry have also accelerated the discovery and optimization of macrocyclic peptide libraries.
The unique properties of macrocyclic peptides have led to their widespread application across various scientific disciplines:
* Drug Discovery: Macrocyclic peptides are highly sought after in pharmaceutical research.作者：P Fang·2024·被引用次数：49—In this tutorial review, diverse state-of-the-artmacrocyclizationmethodologies and techniques forpeptidesand peptidomimetics are surveyed and discussed. Their enhanced stability and ability to mimic protein-protein interactions make them promising candidates for therapeutic agents targeting diseases where traditional small molecules or linear peptides fall short. They can act as enzyme inhibitors, receptor agonists or antagonists, and antimicrobial agents.
* Peptidomimetics: Macrocyclization is a key strategy for designing peptidomimetics—compounds that mimic the biological activity of peptides but possess improved drug-like properties作者：FJ Adrio·2024·被引用次数：1—Herein, we report an efficient diastereoselectivemacrocyclizationstrategy for the synthesis of cyclicpeptidesusing 1,3-dipolar cycloaddition of azomethine ....
* Nanomaterials: The well-defined structures of cyclic peptides can be exploited in the design of novel nanomaterials, with applications in areas like drug delivery systems and biosensors.
* Biotechnology: Macrocyclic peptides are valuable tools in molecular biology, for instance, in mRNA display techniques for discovering high-affinity ligands for specific protein targets.
Despite significant progress, challenges remain in peptide macrocyclization.作者：F Smith·2024·被引用次数：12—Synthetic methods that enable the macrocyclisation ofpeptidesfacilitate the development of more effective therapeutic and diagnostic tools. Developing highly efficient and site-selective methods that can be applied to longer, unprotected peptides is an ongoing area of research作者：MC Fleming·2023·被引用次数：27—mRNA display of macrocyclicpeptideshas proven itself to be a powerful technique to discover high-affinity ligands for a protein target.. Furthermore, understanding and controlling the conformational preorganization of linear peptide precursors is crucial for improving cyclization efficiency作者：TL Cheung·2024·被引用次数：8—An efficient strategy is discovered forpeptidecyclization and functionalization toward lanthanide probe via three components intermolecular crosslinking.. The integration of computational methods with experimental design continues to accelerate the discovery of novel macrocyclization strategies and the design of peptides with desired properties. As synthetic methodologies evolve and our understanding of peptide structure-function relationships deepens, peptide macrocyclization is poised to play an even more significant role in advancing medicine and materials science.
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