is-ghrelin-a-peptide-hormone The solid-phase peptide synthesis of lantibiotics represents a critical advancement in accessing these complex antimicrobial peptides作者：PJ Knerr·2013·被引用次数：70—Therefore, we drew upon previous total syntheses oflantibioticsvia 9-fluorenylmethoxycarbonyl-basedsolid-phase peptide synthesis(Fmoc-SPPS) to construct 1 .... Lantibiotics, a class of ribosomally synthesized and post-translationally modified peptides, are characterized by their unique thioether cross-links, which are crucial for their structural stability and potent bioactivity. The application of solid-phase peptide synthesis (SPPS) techniques has revolutionized the ability to create both natural lantibiotics and their modified analogues, offering a powerful tool for studying their mechanisms of action, developing new therapeutic agents, and understanding their role in bacterial defense.
Traditionally, the chemical synthesis of peptides, especially those with intricate modifications like lantibiotics, posed significant challenges. The presence of multiple thioether bridges, unique amino acid residues, and often complex ring structures made traditional solution-phase methods laborious and inefficient, yielding low overall quantities.Solid-Phase Peptide Synthesis of Analogues of the N- ... Solid-phase peptide synthesis overcomes many of these limitations by anchoring the growing peptide chain to an insoluble solid support. This allows for the sequential addition of amino acids and reagents, with excess reagents and byproducts being easily washed away after each step. This iterative process is highly amenable to automation and significantly improves yields and purity, making the total synthesis of the lantibiotic lactocin S and other complex peptides more feasible.
The ability to perform solid-phase peptide synthesis of analogues of the lantibiotic nisin, for example, allows researchers to systematically probe the structure-activity relationships of these moleculessolid-phase-peptide-synthesis-and-its-applications-in-- .... By altering specific amino acids or the positions and types of thioether cross-links, scientists can investigate how these modifications affect the lantibiotic's binding to its target (often lipid II), its antimicrobial spectrum, and its potencyFour analogues of lactocin S, an antimicrobiallantibiotic peptideproduced by Lactobacillus sakei L45, have been generated usingsolid-phase peptide.... This is vital for the development of next-generation antibiotics with improved efficacy or reduced resistance.
Several lantibiotics have been a focus of synthetic efforts, each presenting unique challenges and opportunities:
* Nisin: One of the most well-known lantibiotics, nisin is widely used as a food preservative. Its synthesis, particularly the creation of its A-ring analogues, has been a significant area of research using solid-phase peptide synthesis. Researchers have successfully synthesized analogues with replacements for key residues like Dha (dehydroalanine), demonstrating the versatility of SPPS in generating structurally diverse nisin variants.Hybrid Lantibiotics: Combining Synthesis and Biosynthesis
* Lactocin S: This lantibiotic, produced by *Lactobacillus sakei*, has been a prime target for solid-phase peptide synthesis. Studies have detailed the synthesis of the lantibiotic lactocin S using peptide cyclizations on solid phase, achieving respectable overall yields. The development of strategies for intramolecular cyclization on the solid support has been key to forming the characteristic thioether rings of lactocin S.
* Lacticin 481: The solid-supported chemical synthesis of lacticin 481, and its analogues, has also been achievedSynthesis of the Lantibiotic Lactocin S Using Peptide .... This work often builds upon established Fmoc-based SPPS protocols, demonstrating the adaptability of these methods to different lantibiotic scaffolds. The synthesis of lacticin 481 highlights the potential for creating novel versions with tailored properties.
* Two-component Lantibiotics: Some lantibiotics, like lacticin 3147, are produced as two-peptide systems. The solid-phase syntheses of both peptides of a two-component lantibiotic have been reported, showcasing the capability of SPPS to prepare these complex systems, which often require specific interactions between the components for full activity.
The successful implementation of solid-phase peptide synthesis for lantibiotics relies on several key methodological considerations:
* Resin Choice: The selection of the solid support resin is crucialFour analogues of lactocin S, an antimicrobiallantibiotic peptideproduced by Lactobacillus sakei L45, have been generated usingsolid-phase peptide.... Chlorotrityl polystyrene resin, for instance, has been employed for the synthesis of lactocin S, facilitating efficient cleavage and cyclizationSynthesis and biological evaluation of the... - ERA.
* Protecting Group Strategies: Fmoc (9-fluorenylmethoxycarbonyl) chemistry is a widely adopted strategy for SPPS, including for lantibiotics like nisin and lacticin 481作者：VR Pattabiraman·2008·被引用次数：70—...solid- and solution-phase peptide synthesis. Chemically synthesized Lan-A2 (2) exhibits synergistic biological activity similar to natural .... This strategy allows for selective deprotection and coupling steps.
* Cyclization Strategies: Forming the characteristic thioether cross-links is a critical step. This can involve intramolecular cyclization reactions performed on the solid support after the linear peptide is assembled. Techniques like ring-closing metathesis have also been integrated with SPPS for constructing specific cyclic structures within lantibiotics.(PDF) Synthesis of the Lantibiotic Lactocin S Using Peptide ...
* Incorporation of Modified Amino Acids: The synthesis often requires the incorporation of non-standard amino acids, such as lanthionine, or precursors that can be converted into these modified residues. Libraries of orthogonally protected lanthionine building blocks ready for incorporation into SPPS have been developed.
* Yields and Purity: While SPPS significantly improves efficiency, achieving high overall yields for complex molecules like lantibiotics remains a challengeSolid‐Supported Synthesis and Biological Evaluation of .... Optimization of coupling efficiencies, deprotection protocols, and cleavage conditions is continuously pursued to maximize the output of pure, functional peptides.
The advances in solid-phase peptide synthesis have opened new avenues for lantibiotic research and development. The ability to produce these peptides synthetically facilitates:
* Drug Discovery: Creating diverse libraries of lantibiotic analogues for screening against drug-resistant bacteria.
* Mechanistic Studies: Synthesizing specifically modified peptides to elucidate their molecular targets and modes of action.
* Biotechnology: Developing novel antimicrobial agents for various applications, including medicine, agriculture, and food safetyThe research details thetotal synthesis of the lantibiotic lactocin S, a natural peptide from Lactobacillus sakei, through solid-phase peptide cyclizations ....
* Hybrid Approaches: Combining chemical synthesis with biosynthetic methods to create hybrid lantibiotics with enhanced properties.
In conclusion, solid-phase peptide synthesis has become an indispensable tool for the chemical synthesis of lantibioticsSynthesis of the lantibiotic lactocin S using peptide .... By enabling the efficient construction of these complex peptides and their analogues, SPPS continues to drive innovation in the field of antimicrobial research, paving the way for new therapies and a deeper understanding of these fascinating natural products"Solid-Phase Peptide Synthesis of Analogues of the N- ....
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