solid-support-peptide-synthesis The total synthesis of complex peptides, such as the lantibiotic Mersacidin, represents a significant challenge and achievement in organic chemistry.Solid Phase Peptide Synthesis (SPPS) explained While Mersacidin's potent antibacterial activity against Gram-positive bacteria makes it a compelling target, its intricate polycyclic structure, featuring lanthionine bridges, necessitates sophisticated synthetic strategies. Solid-phase peptide synthesis (SPPS) has emerged as a cornerstone methodology for tackling such complex molecules, offering a robust and scalable approach to assemble amino acids sequentially on a solid support. This article explores the principles and applications of SPPS in the context of Mersacidin's total synthesis, highlighting the key considerations and advancements in this field.The Lantibiotic Mersacidin Is an Autoinducing Peptide - PMC
Mersacidin is a 20-residue polycyclic lantibiotic peptide characterized by its unique post-translational modifications, most notably the presence of lanthionine and methyllanthionine residues. These sulfur-bridged amino acids are formed through the cyclization of cysteine residues with dehydroalanine or dehydrobutyrine, respectively. The formation of these cross-links is crucial for Mersacidin's three-dimensional structure and its biological activity, which involves targeting Lipid II, a precursor in bacterial cell wall biosynthesis. The inherent complexity arising from these modified amino acids and their specific arrangement presents a formidable hurdle for chemical synthesis.
Solid-phase peptide synthesis, pioneered by R2025年8月6日—A convergent assembly of the cyclicpeptidescaffold and a single global hydrogenolysis deprotection operation provided mannopeptimycin α and β.. Bruce Merrifield, revolutionized peptide chemistry by immobilizing the growing peptide chain onto an insoluble polymer resinTotal Synthesis of Mannopeptimycins α and β | Request PDF. This strategy allows for excess reagents to be used and washed away easily, simplifying purification at each step and enabling automationPeptide Chemistry | The Journal of Organic ... - ACS Publications. The general SPPS process involves:
1. Resin Attachment: The C-terminal amino acid of the target peptide is covalently attached to a solid support, typically a functionalized polystyrene resin.
2Allthe samples were prepared in an analogous manner first dissolving peptide ...Solid-phase peptide synthesis, a practical approach; IRL Press: Oxford, 1989.. Deprotection: The N-terminal protecting group (commonly Fmoc or Boc) of the attached amino acid is removed.作者：L Lepsa·2000·被引用次数：271—Since thesolid-phasemethod is very expedient, syn- thesis of the corresponding isomer, containing the. C-terminal D-amino acid, is also recommended. Using.
3作者：R Dickman·2019·被引用次数：51—We have usedsolid-phase peptide synthesisto prepare individual ring A and B structures from nisin, the related lantibiotic mutacin, and synthetic analogues.. Coupling: The next protected amino acid is activated and coupled to the free N-terminus of the growing peptide chain.
4.2025年8月6日—A convergent assembly of the cyclicpeptidescaffold and a single global hydrogenolysis deprotection operation provided mannopeptimycin α and β. Washing: Excess reagents and byproducts are removed by washing the resin.
5.Solid Phase Peptide Synthesis (SPPS) explained Repeat: Steps 2-4 are repeated for each amino acid in the sequence.
6作者：L Lepsa·2000·被引用次数：271—Since thesolid-phasemethod is very expedient, syn- thesis of the corresponding isomer, containing the. C-terminal D-amino acid, is also recommended. Using.. Cleavage: Once the full sequence is assembled, the peptide is cleaved from the resin, and side-chain protecting groups are removed.The purpose of this guide is to provide practical information for planning and executing successfulsolid phase peptidesyntheses.
For Mersacidin, the incorporation of lanthionine and methyllanthionine residues requires specialized building blocks and strategies within the SPPS frameworkUniversity of Alberta. This often involves the use of orthogonally protected lanthionine or methyllanthionine precursors that can be selectively incorporated into the peptide chain and subsequently cyclizedUniversity of Alberta.
The total synthesis of Mersacidin via SPPS is not without its challenges. Key among these are:
* Incorporation of Modified Amino Acids: Synthesizing and incorporating the lanthionine and methyllanthionine rings requires careful planning. This often involves pre-synthesized, orthogonally protected lanthionine or methyllanthionine units that can be integrated into the peptide sequence during SPPS. These units must be stable under the coupling and deprotection conditions used for standard amino acidsThe role of chemical synthesis in developing RiPP antibiotics.
* Cyclization Strategies: The formation of the thioether bridges is a critical step. While some approaches rely on post-synthesis modifications after cleavage from the resin, others aim to achieve cyclization on the solid support itself, which can be more efficient and less prone to side reactionsThe research details thetotal synthesis of the lantibiotic lactocin S, a natural peptide from Lactobacillus sakei, through solid-phase peptide cyclizations ....
* Peptide Solubility and Aggregation: As the peptide chain grows on the resin, solubility issues and aggregation can arise, hindering efficient coupling and leading to truncated or deletion sequences. Careful selection of resins, solvents, and coupling reagents is essential to mitigate these problems.Solid-phase peptide synthesis: from standard procedures ...
* Stereochemical Control: Ensuring the correct stereochemistry of amino acids and the lanthionine bridges is paramount for biological activity. This requires meticulous control over reaction conditions and the use of stereochemically pure building blocks.Chemical Synthesis and Biological Activity of Analogues of the ...
Advancements in SPPS, such as the development of more efficient coupling reagents, novel resin chemistries, and improved protecting group strategies, have significantly contributed to the successful total synthesis of complex peptides like Mersacidin and other lantibiotics such as nisin and mutacin. The exploration of hybrid approaches, combining chemical synthesis with biosynthetic methods, also offers promising avenues for producing these valuable natural products.
The total synthesis of Mersacidin exemplifies the power and sophistication of modern chemical synthesis, particularly solid-phase peptide synthesis. By enabling the stepwise assembly of amino acids on a solid support, SPPS provides a tractable route to molecules with intricate structures and significant biological relevance. Overcoming the challenges associated with the incorporation of modified amino acids and achieving efficient cyclization requires continuous innovation in synthetic methodologyLanthipeptides: chemical synthesis versus in vivo .... As research progresses, the ability to synthesize complex lantibiotics like Mersacidin will undoubtedly play a crucial role in the development of new therapeutic agents and a deeper understanding of peptide chemistry.作者：T Denoël·2014—2.3.4Synthesisfrom dehydroalanine. An orthogonally protected Lan suitable forsolid phase peptide synthesis(SPPS) was synthesized by Probert et al. to ...
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