Peptide cyclizationstrategies Peptide cyclization is a critical modification technique that transforms linear peptides into cyclic structures, thereby enhancing their properties and overcoming inherent limitations.作者：M Schmidt·2017·被引用次数：57—This review focusses solely onenzyme-catalyzed peptide ligationresulting in head-to-tail (N single bond C) cycles with a native peptide bond at the ligation ... This process involves forming a covalent bond that closes the peptide chain, leading to conformational constraints and significantly improved biological activity. Cyclic peptides are a vital pool of therapeutics, particularly antibiotics, and are drawing wide attention as potential modulators of biomolecular interactions due to their increased binding affinity and selectivity towards target moleculesCyclization is alsoused in synthetic peptidesto impose a desired conformation in the peptide, especially when the peptide is based on a portion of a much .... Understanding the diverse methodologies and applications of peptide cyclization is crucial for advancing drug discovery and biochemical researchThree Methods for Peptide Cyclization Via Lactamization.
The primary drivers for peptide cyclization stem from the limitations of linear peptides, such as poor stability against proteases and limited conformational rigidity. Cyclization addresses these issues by introducing conformational constraints to the polypeptide backbone, which significantly decreases its flexibility. This rigidity can lead to several key advantages:
* Enhanced Biological Activity: By imposing a specific three-dimensional shape, cyclic peptides can achieve a more optimized fit with their biological targets. This improved binding potency and selectivity are crucial for therapeutic efficacy.
* Increased Protease Stability: The cyclic structure often shields the peptide bond from enzymatic degradation, leading to a longer in vivo half-life and reduced clearance rates.
* Improved Pharmacokinetic Properties: Enhanced stability and binding can translate into better absorption, distribution, metabolism, and excretion (ADME) profiles, making cyclic peptides more suitable for drug developmentPeptide Cyclization at High Concentration - The Raj Group.
* Bridging Chemical Space: Cyclic peptides can bridge the gap between small molecules and larger biologics like antibodies, offering a unique chemical space for designing molecules with high binding capabilities and specific therapeutic actions.Cyclic peptides are useful for optimization of peptides, such as increase binding potency/selectivity, enhance protease stability.
These benefits have led to the development of cyclic peptides for various applications, including anti-aging therapies, wound healing, and as potent biochemical tools.
The field of peptide cyclization employs a wide array of strategies, broadly categorized into chemical and enzymatic approaches. These methods aim to form new peptide bonds or other covalent linkages within the peptide chain.
#### Chemical Cyclization Strategies
Chemical methods often involve the activation of terminal or side-chain functional groups to promote intramolecular bond formation.Peptide Cyclisation Methods Some prominent strategies include:
* Lactamization: This common approach involves forming an amide bond between an amine and a carboxyl group. It can be achieved through various coupling reagents and often follows solid-phase peptide synthesis. Different strategies exist for lactamization, allowing for the creation of cyclic peptides via the coupling of amine and carboxyl termini in the solution phase or through solid-phase synthesis followed by solution-phase macrocyclization.Macrocyclization strategies for cyclic peptides and ... - PMC
* Native Peptide Cyclization (NPC): This chemoselective method enables intramolecular peptidyl ligation without the need for pre-modification of the peptide termini. It is particularly useful for creating cyclic peptides with a native peptide bond at the ligation site, mimicking naturally occurring cyclic peptides.
* Stapled Peptides: While not strictly cyclization in the traditional sense, stapled peptides involve introducing a hydrocarbon linker to stabilize a specific helical conformation, often mimicking protein-protein interaction interfaces作者：HC Hayes·2021·被引用次数：133—The cyclisation of polypeptidescan play a crucial role in exerting biological functions, maintaining stability under harsh conditions and conferring ....
* Isothiocyanate-Mediated Cyclization: This method utilizes isothiocyanate chemistry for cyclization, often employed in phage display libraries to generate cyclic peptides with high affinity for protein targets.
* Acylammonium Species: Unconventional approaches using acylammonium species generated from readily available reagents offer efficient pathways for peptide cyclizationGoing around in circles, the art of peptide cyclization.
These chemical methods can be performed in solution or on solid support, with variations in concentration and reagent choice influencing cyclization efficiency. For instance, methodologies exist for synthesizing cyclic peptides at high concentrations without the formation of undesirable dimers or oligomers.
#### Enzymatic and Chemoenzymatic Approaches
Enzymatic methods leverage the specificity and efficiency of enzymes to catalyze peptide bond formation, often resulting in native peptide bonds within the cyclic structure.
* Enzyme-Catalyzed Peptide Ligation: Specific enzymes can catalyze intramolecular peptide ligation, typically forming head-to-tail (N-C) cycles with a native peptide bond.Peptide Cyclization by the Use of Acylammonium Species This approach is particularly valuable for creating cyclic peptides that closely resemble natural products.
* Sortase A-Catalyzed Cyclization: Sortase A, a bacterial transpeptidase, can be harnessed for chemoenzymatic synthesis of macrocyclic peptides and glycopeptides, mediating head-to-tail cyclization.
* Self-Cyclization via Proteases: Certain proteases exhibit unusual enzymatic transpeptidation activity, enabling the natural cyclization of peptide backbones.
* Chemoenzymatic Tandem Cyclization: This approach combines chemical and enzymatic steps in a one-pot reaction to efficiently synthesize complex cyclic peptides, including bicyclic peptides.
Enzymatic methods are often favored for their high selectivity, mild reaction conditions, and ability to produce peptides with native linkages, which can be advantageous for biological applicationsThree Methods for Peptide Cyclization Via Lactamization.
The efficiency of peptide cyclization is a critical parameter influenced by several factors, including:
* Ring Size: The size of the resulting ring significantly impacts the ease of cyclization. Smaller rings can be entropically disfavored, while very large rings may also present challenges12小时前—Cyclic peptides exhibit advantages in binding protein targetswith high affinity and competency in inhibiting protein-protein interactions.. Studies analyzing millions of peptide sequences have revealed the effect of ring size on cyclization efficiencyCyclic peptides are useful for optimization of peptides, such as increase binding potency/selectivity, enhance protease stability..
* Peptide Sequence: The amino acid sequence itself plays a crucial role.作者：X Jia·2023·被引用次数：20—The backbones of peptides and proteins are naturally cyclisedby a certain group of proteases with unusual enzymatic transpeptidation activity ( ... Certain sequences may be more prone to intramolecular cyclization due to favorable conformational propensities or the presence of reactive side chains.
* Solvent: The choice of solvent can profoundly affect the conformation of the peptide and the reactivity of the functional groups, thereby influencing cyclization rates and yields.
* Concentration: As mentioned, high concentrations can sometimes lead to intermolecular side reactions (dimerization or oligomerization) instead of the desired intramolecular cyclization. Optimized concentration ranges are therefore essential.Enzyme-catalyzed peptide cyclization
* Methodology: The specific chemical or enzymatic strategy employed will inherently have different efficiencies and limitations based on the chemistry involved and the enzyme's catalytic power.
Cyclic peptides are emerging as a powerful class of therapeutics and research tools. Their inherent stability, potent biological activity, and ability to interact with challenging biological targets make them attractive alternatives to traditional small molecules and large biologics. Ongoing research into novel cyclization methodologies, including rapid synthesis inspired by natural product biosynthesis and automated platforms, promises to expand the scope and accessibility of cyclic peptide development.作者：H Chen·2023·被引用次数：20—We introduce NativePeptide Cyclization(NPC), a chemoselective method enabling intramolecular peptidyl ligation without the need for premodification. As our understanding of their structure-activity relationships deepens, cyclic peptides are poised to play an increasingly significant role in addressing unmet medical needs and advancing our understanding of biological processes.
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