solid-phase-peptide-synthesis-mersacidin-total-synthesis The total synthesis of Mersacidin represents a significant challenge and achievement in peptide chemistry, particularly when employing solid-phase peptide synthesis (SPPS). Mersacidin, a potent lantibiotic antibiotic produced by *Bacillus* species, is characterized by its complex structure, including lanthionine bridges, which are post-translationally modified amino acids crucial for its antimicrobial activity. The intricate nature of these modifications and the peptide sequence itself necessitates sophisticated synthetic strategies to achieve a complete and total synthesis.
Lantibiotics, a class of ribosomally synthesized and post-translationally modified peptides (RiPPs), are distinguished by the presence of lanthionine (Lan) and methyllanthionine (MeLan) residues, formed from dehydration and subsequent cyclization of cysteine residues. Mersacidin, a 20-amino acid peptide, is a prime example, exhibiting broad-spectrum antibacterial activity. Its structure and mechanism of action, which involves binding to lipid II, the precursor of peptidoglycan biosynthesis, have made it a subject of intense researchChemical Synthesis and Biological Activity of Analogues of the .... The ability to synthesize Mersacidin and its analogues chemically is vital for exploring structure-activity relationships, developing novel antimicrobial agents, and understanding its biological functionsPeptide Chemistry | The Journal of Organic ... - ACS Publications.
Solid-phase peptide synthesis (SPPS) has revolutionized peptide chemistry by allowing for the stepwise assembly of peptide chains on an insoluble solid support. This method offers significant advantages over traditional solution-phase synthesis, including simplified purification steps (washing away excess reagents and byproducts) and the potential for automation. For complex peptides like Mersacidin, SPPS provides a robust framework for building the peptide backboneSolid-phase peptide synthesis: from standard procedures .... However, the incorporation of modified amino acids and the formation of thioether bridges present unique challenges that require specialized reagents and optimized protocols within the SPPS methodology.Solid Phase Peptide Synthesis (SPPS) explained
The total synthesis of Mersacidin via SPPS is complicated by several factors intrinsic to lantibiotics:
* Lanthionine Ring Formation: The formation of lanthionine and methyllanthionine bridges requires precise control over cyclization reactionsChemical Synthesis of the Lantibiotic Lacticin 481 Reveals the .... These modifications are not standard amino acids and must be either pre-synthesized and incorporated or formed *in situ* on the solid support, often involving dehydration of serine or threonine residues followed by nucleophilic attack by cysteine.(PDF) Synthesis of the Lantibiotic Lactocin S Using Peptide ...
* Peptide Sequence Complexity: Mersacidin's specific amino acid sequence, including unusual residues and stereochemistry, demands careful selection of protecting groups and coupling reagents to ensure efficient and accurate chain elongation作者：PJ Knerr·2013·被引用次数：70—Therefore, we drew upon previoustotalsyntheses of lantibiotics via 9-fluorenylmethoxycarbonyl-basedsolid-phase peptide synthesis(Fmoc-SPPS) to construct 1 ....
* Cleavage and Deprotection: Once the peptide chain is assembled on the resin, cleavage from the solid support and removal of all protecting groups must be carried out under conditions that preserve the integrity of the peptide and its modified residues. Harsh conditions can lead to side reactions or degradation.
* Yield and Purity: Achieving high yields and purity in the total synthesis of such a complex molecule is a significant hurdle.作者：PJ Knerr·2013·被引用次数：70—Therefore, we drew upon previoustotalsyntheses of lantibiotics via 9-fluorenylmethoxycarbonyl-basedsolid-phase peptide synthesis(Fmoc-SPPS) to construct 1 ... Multiple steps in SPPS, each with its own potential for incomplete reactions or side products, can lead to a low overall yield of the target peptide.
Researchers have employed various strategies to overcome these challenges in the solid-phase peptide synthesis of Mersacidin and related lantibiotics. This often involves adapting established SPPS protocols, such as Fmoc (9-fluorenylmethoxycarbonyl) chemistry, which allows for mild deprotection conditions compatible with sensitive functional groups. Specialized building blocks for lanthionine precursors or protected lanthionine residues may be synthesized and incorporated during the SPPS cycle. Furthermore, innovative approaches to promote efficient cyclization and bridge formation on the solid support are continuously being developed. The goal is to achieve a complete synthesis that not only produces the correct peptide sequence but also accurately replicates the native post-translational modifications.Orthogonally Protected Lanthionines: Synthesis and Use ...
The total synthesis of Mersacidin using solid-phase peptide synthesis is a testament to the advancements in synthetic organic chemistry. It allows for the creation of this important lantibiotic from basic chemical components, providing researchers with essential tools to study its biological activity and explore its potential as a therapeutic agent. While challenging, the successful solid-phase peptide synthesis of Mersacidin and other complex peptides underscores the power of chemical synthesis in accessing valuable biomolecules作者：S Schmitz·2006·被引用次数：97—The lantibiotic (lanthionine-containing antibiotic)mersacidinis an antimicrobialpeptideconsisting of 20 amino acids and is produced by Bacillus sp..
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