solid-phase synthesis of lanthionine-containing peptides lanthionine peptides - colagen-peptide with Mastering the Solid-Phase Synthesis of Lanthionine-Containing Peptides

solid-phase-peptide-synthesis-duramycin-total-synthesis The intricate world of peptide chemistry often demands the incorporation of unusual amino acids to impart unique functionalities and structures to peptide molecules. Among these, lanthionine stands out as a key post-translational modification found in a class of ribosomally synthesized peptides known as lantibiotics. The solid-phase synthesis of lanthionine-containing peptides has emerged as a powerful tool for chemists aiming to construct these complex molecules and their analogues, a significant endeavor in the field of peptide synthesisMolecular Recognition of Lipid II by Lantibiotics - UCL Discovery. This article delves into the methodologies, challenges, and advancements in achieving this crucial synthetic goal, underpinned by expert knowledge and extensive research.

Understanding Lanthionine and its Significance

Lanthionine is a thioether amino acid formed through the cyclization of a cysteine residue with a dehydroalanine (Dha) or dehydrobutyrine (Dhb) residue. This unique sulfur bridge is a hallmark of lantibiotics, a diverse group of bacteriocins with potent antimicrobial activitySolid-Phase Synthesis of C-Terminus Cysteine Peptide Acids. The presence of lanthionine peptides confers structural rigidity and enhanced stability to these natural products, contributing to their biological efficacy. Consequently, the ability to synthesize peptides containing lanthionine is paramount for exploring the structure-activity relationships of lantibiotics and for developing novel therapeutic agents.Solid Phase Synthesis and Applications of Sulfur Bridged ...

The Solid-Phase Approach: A Cornerstone of Peptide Synthesis

The advent of solid-phase peptide synthesis (SPPS) revolutionized peptide chemistry by anchoring the growing peptide chain to an insoluble resin support. This methodology simplifies purification steps, allowing for efficient iterative coupling and deprotection cycles. Applying this technique to the synthesis of peptides containing unusual modifications like lanthionine presents specific challenges. Early research in the synthesis of lanthionine peptides often involved solution-phase construction of the modified amino acid, followed by its incorporation into the growing peptide chain during SPPS. However, the development of more sophisticated solid-phase peptide synthesis strategies has enabled the direct formation of lanthionine bridges on-resin, streamlining the process.

Key Strategies in Solid-Phase Lanthionine Synthesis

Several strategies have been developed to facilitate the solid-phase synthesis of lanthionine-containing peptides. A recurring theme is the utilization of orthogonally protected lanthionines.作者：SN Mthembu·2022·被引用次数：12—Lanthionine Peptides by S-Alkylationwith · Substituted Cyclic Sulfamidates Promoted by Activated Molecular · Sieves: Effects of the Sulfamidate ... This approach involves synthesizing lanthionine building blocks with protecting groups that can be selectively removed under different conditions作者：R Dickman·2019·被引用次数：51—28 We have developed a powerfulsolid-phase peptide synthesis (SPPS) strategyfor the synthesis of lanthionine- containing peptides.29 This is .... This orthogonality is crucial for controlling the cyclization reaction and preventing unwanted side reactions during the stepwise assembly of the peptideSolid Phase Synthesis and Applications of Sulfur Bridged ....

For instance, various protecting group combinations, such as Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), and allyl or methyl esters, have been employed. The choice of protecting groups depends on the overall synthetic strategy and the compatibility with other reagents used in SPPS. Pioneering work by researchers like Probert and colleagues demonstrated the utility of orthogonally protected lanthionine for combinatorial and SPPS.作者：PJ Knerr·2013·被引用次数：70—Here,solid-supported chemicalsynthesisenabled the totalsynthesisof the lantibiotic lacticin 481 and analoguescontainingcross-linkswithnon-native ...

Another significant advancement is the development of methods for directly forming the thioether bond on the solid support. This often involves the S-alkylation of a cysteine residue with a proximate dehydroamino acid precursor, or vice versa. Various reagents and conditions have been explored to optimize this cyclization step, aiming for high chemoselectivity and stereospecificity.作者：SN Mthembu·2022·被引用次数：12—Lanthionine Peptides by S-Alkylationwith · Substituted Cyclic Sulfamidates Promoted by Activated Molecular · Sieves: Effects of the Sulfamidate ... Notably, research has focused on green and efficient methods for this crucial linkage formation2023·被引用次数：3—The strategy involves thesolid-phase synthesis of sulfamidate-containing peptidesfollowed by late-stage intra- molecular cyclization. This ....

Specific Methodologies and Examples

The total solid phase synthesis of lantibiotics and their analogues has been a primary driving force behind these synthetic developments作者：MFM Mustapa·被引用次数：1—The aim of this project is to develop the foun- dation of thetotal solid phase synthesis of lantibioticsand their analogues by investi- gating the possibility .... For example, the synthesis of enkephalin analogues has served as a platform to demonstrate all-solid-phase approaches applicable to lanthionine formation, particularly in less sterically hindered peptides.

Furthermore, the solid-phase synthesis of peptides containing L,L-lanthionine sulfoxide has been achieved by leveraging established Fmoc/tBu chemistryOrthogonally protected lanthionines: synthesis and use for .... This highlights the adaptability of SPPS protocols to incorporate various forms of lanthionine. The synthesis of lantibiotic fragments, such as those found in nisin, has also been successfully achieved using SPPS, employing methodologies for solid-phase synthesis of the overlapping lanthionine bridges.作者：S Bregant·2005·被引用次数：101—Synthesis of Peptides Containing Overlapping Lanthionine Bridges on the Solid Phase: An Analogue of Rings D and E of the Lantibiotic Nisin. Organic Letters ...

Researchers have also explored late-stage synthetic approaches, where the lanthionine bridge is formed towards the end of the peptide synthesis. This strategy can be particularly advantageous for complex architectures. The successful synthesizing lanthionine-containing peptides via S-alkylation of cysteine with activated cyclic sulfamidates showcases novel pathways for efficient bridge formation.A facile method for the direct synthesis of lanthionine ...

Challenges and Future Directions

Despite significant progress, challenges remain in the solid-phase synthesis of complex lanthionine-containing peptidesWhilst developing a strategy for thesolid-phase synthesis of lanthionine-containing peptides, we became aware of some problems with a previously published .... These include achieving efficient cyclization in sterically demanding regions, managing side reactions, and obtaining high overall yields.A Late-Stage Synthetic Approach to Lanthionine-Containing ... The development of improved protecting group strategies and more robust coupling and cyclization chemistries continues to be an area of active research.

The exploration of solid-phase synthesis of sulfamidate-containing peptides and the use of preformed, selectively protected lanthionines as building blocks further underscore the ongoing innovation in this field. Ultimately, the ability to precisely construct peptides containing these unique sulfur bridges opens doors to new possibilities in drug discovery, diagnostics, and biochemical research. As synthetic methodologies continue to evolve, the solid-phase realm will remain central to unlocking the full potential of lanthionine-modified peptides.