Epimerizationof tetracycline Peptide epimerization, a chemical conversion that transforms an epimer into its chiral partner, is a critical challenge in peptide synthesis作者：D Crich·2009·被引用次数：119—This method generates highly reactive thioesters in situ, which then react with the amine to formpeptidebonds, and tolerates the presence of .... This process, also known as racemization, can significantly impact the purity and biological activity of synthetic peptidesDevelopment of Two Complementary Epimerization .... Understanding the mechanisms behind peptide epimerization and employing strategies to prevent it are vital for researchers and chemists working with peptide-based therapeutics, diagnostics, and materials. The presence of D-amino acid residues, often isolated from microorganisms, highlights the natural occurrence and synthetic implications of epimerization.
Epimerization refers to a change in the stereochemical configuration at a single chiral center, resulting in the formation of a diastereomer. In the context of peptide synthesis, this typically involves the α-carbon of an amino acid residue.作者：D Crich·2009·被引用次数：119—This method generates highly reactive thioesters in situ, which then react with the amine to formpeptidebonds, and tolerates the presence of ... This phenomenon is closely related to racemization, where a chiral compound is converted into a mixture of enantiomers or diastereomers. The rate and likelihood of epimerization are influenced by several factors, including the specific amino acid sequence, the solvent used, and the reaction conditions.The minimization of amino acidracemizationduring coupling is also of vital importance to avoidepimerizationin the finalpeptideproduct. For instance, residues like Valine (Val) or Isoleucine (Ile) are known to be more prone to epimerization, particularly in polar solvents.
The core issue arises during peptide bond formation, which necessitates the activation of the carboxyl group of an incoming amino acid. This activation step can inadvertently create conditions that favor the abstraction of the α-proton, leading to the formation of a transient enolate intermediate. This intermediate can then be reprotonated from either face, resulting in the inversion of configuration at the α-carbon. Furthermore, the formation of oxazolone intermediates during coupling reactions can also contribute to epimerization during peptide couplings. Detecting and quantifying epimerization during synthesis is crucial for ensuring the integrity of the final peptide product.Solid Phase Peptide Synthesis of the Fragment BPC 157 of Human ...
Several factors can exacerbate peptide epimerization during synthesis. The C-terminal amino acid residue plays a significant role, with some residues being more susceptible to epimerization than others. For example, C-terminal cysteine residues, due to their unique chemical properties, are particularly prone to epimerization, necessitating specialized strategies to achieve epimerization-free preparation of C-terminal Cys peptides.
The choice of coupling reagents and reaction conditions is paramount. Harsh activation methods or prolonged reaction times can increase the risk of epimerization. Certain peptide coupling reagents have been developed specifically to minimize or eliminate this problem, offering epimerization-free peptide synthesis. Moreover, the presence of unnatural amino acids or modifications within the peptide chain can also influence the propensity for epimerization.作者：AF Spatola·1996·被引用次数：80—During our synthesis of cyclicpeptidemixtures, C-terminalepimerizationwas identified as a problem during chain elongation. This was significantly overcome ... For instance, glycosylated amino acids can exhibit enhanced epimerization under common peptide coupling conditions used for preparing O-linked glycopeptides.Epimerization of Peptide
Given the detrimental effects of epimerization on peptide function, significant research has focused on developing methods to achieve epimerization-free synthesisAn approach to cyclic peptide libraries: Reducing .... These strategies often involve careful selection of coupling reagents, protective groups, and reaction conditions.
One approach involves modifying the activation and ligation of peptides, particularly those with racemization-prone residues at the C-terminus, such as phenylglycineEpimerization‐Free C‐Terminal Peptide Activation - 2013. Specialized resins and pseudoproline structures have been employed to achieve epimerization-free direct preparation of peptides, including those containing C-terminal cysteine.
Innovative coupling reagents and methodologies are continuously being developed. For example, reagents that facilitate O-to-O acyl transfer for epimerization-free peptide C-terminal activation, or those that utilize allenone-mediated reactions, have shown promise in forming peptide bonds with minimal or no epimerization.作者：D Crich·2009·被引用次数：119—This method generates highly reactive thioesters in situ, which then react with the amine to formpeptidebonds, and tolerates the presence of ... Solid-phase peptide synthesis (SPPS) techniques have also seen advancements aimed at achieving efficient, epimerization-free synthesis, including the development of novel, safe, and cost-effective coupling reagents.作者：Z Zhang·2001·被引用次数：1—It is well known thatpeptide bond formation requires the activation of the carboxyl group of the incoming amino acid. In this activation step, the α-carbon of ... Strategies that enable the assembly of peptides from the N to C directions without observable epimerization are also being explored.Epimerization-free access to C-terminal cysteine peptide acids ...
Peptide epimerization remains a significant hurdle in achieving high-purity synthetic peptides. The process of epimerization, closely tied to racemization, can compromise the intended biological or chemical properties of the peptide.Epimerisation is basically a chemical conversionthat includes the transformation of an epimer into another epimer or its chiral partner. However, a growing array of sophisticated chemical strategies and reagents are available to combat this challenge. By understanding the underlying mechanisms and carefully selecting synthetic approaches, researchers can effectively minimize or eliminate epimerization, ensuring the successful production of functional and pure peptide molecules for diverse applications.
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