solid-phase synthesis of lanthionine-containing peptides peptides - collagen-5-peptides solid phase Mastering the Solid-Phase Synthesis of Lanthionine-Containing Peptides

solid-state-peptide-synthesis The intricate world of peptide synthesis has seen remarkable advancements, particularly in the construction of peptides featuring unusual amino acids like lanthionine. Solid-phase synthesis of lanthionine-containing peptides has emerged as a cornerstone technique, offering a robust and versatile platform for accessing these complex molecules. This article delves into the methodologies, challenges, and significant achievements in the field, drawing upon decades of research and development作者：S Bregant·2005·被引用次数：101—We then used this orthogonally protected lanthionine in the solid-phase synthesis of an analogue of a fragment of nisin containing its ring C..

Lanthionine, an unusual amino acid characterized by a thioether linkage between a cysteine and a serine or threonine residue, is a defining feature of a class of ribosomally synthesized peptides known as lantibiotics.an analogue of rings D and E of the lantibiotic nisin. - Abstract These peptides, such as the well-known nisin, possess potent antimicrobial activity and are generated through unique post-translational modifications of prepeptides. The ability to synthesize lanthionine-containing peptides is crucial for understanding their biological functions, exploring their therapeutic potential, and developing novel lantibiotics and their analogues.

The Evolution of Lanthionine Incorporation in Solid-Phase Synthesis

Early efforts in the synthesis of lanthionine peptides often relied on solution-phase chemistry, which could be cumbersome and low-yielding, especially for larger or more complex sequences. The advent of solid-phase peptide synthesis (SPPS) revolutionized the field by enabling the sequential addition of amino acids to a solid support, simplifying purification and allowing for automated processes. When applied to lanthionine-containing peptides, SPPS requires careful consideration of orthogonal protecting group strategies to ensure selective formation of the thioether bond without disrupting the peptide chain.

Researchers have developed sophisticated approaches utilizing orthogonally protected lanthionines as key building blocks.US6897289B1 - Peptide synthesis procedure in solid phase These protected amino acids can be incorporated into the growing peptide chain on the solid phase using standard peptide coupling reagents作者：B Mothia·2011·被引用次数：50—A methodology for thesolid-phase synthesis of the overlapping lanthionine bridgesfound in many lantibiotics has been developed.. The key advantage of orthogonal protection is that different protecting groups can be removed sequentially under specific conditions, allowing for controlled cyclization and thioether bond formation at the desired stage of the synthesis. For instance, strategies employing Boc, Fmoc, and Allyl Methyl protecting groups have been described, offering flexibility in their application within combinatorial and solid phase peptide chemistry.A new orthogonal protecting group strategy for lanthionine ...

Key Methodologies and Strategies

Several successful strategies have been reported for the solid-phase synthesis of lanthionine peptides. A common approach involves the S-alkylation of cysteine residues with dehydroalanine (Dha) or dehydrobutyrine (Dhb) residues. This reaction, which forms the characteristic thioether linkage, can be carried out directly on the solid phase after the peptide chain has been assembled.

Another prominent method involves the preparation of lanthionine-containing peptides by incorporating pre-formed, selectively protected lanthionine building blocks.Lanthionine Sulfoxide This bypasses the need for in-situ formation of the thioether bond during peptide assembly and simplifies the process. The successful solid-phase synthesis of peptides containing L,L-lanthionine sulfoxide has been achieved using Fmoc/tBu chemistry, highlighting the precision attainable with such solid-phase synthesis protocols.

The total solid phase synthesis of lantibiotics and their analogues remains a significant goal. This ambitious undertaking requires the development of foundational methodologies that can accommodate the complex structures of these natural products, including multiple thioether cross-links and other post-translational modifications. For example, researchers have explored solid-phase synthesis strategies for the overlapping lanthionine bridges found in many lantibiotics, demonstrating the feasibility of constructing these intricate molecular architectures.

The synthesis of modified lantibiotics has also been a focus作者：S Bregant·2005·被引用次数：101—We then used this orthogonally protected lanthionine in the solid-phase synthesis of an analogue of a fragment of nisin containing its ring C.. For instance, successful preparation of analogues containing replacements for the Dha residue at specific positions has been achieved through solid-phase peptide synthesis.作者：S De Luca·2018·被引用次数：17—A one-pot, high-yield procedure forsynthesizing lanthionine-containing peptideswas developed. It relies on the S-alkylation of ... This allows for the systematic investigation of structure-activity relationships and the discovery of novel biological propertiesSynthesis of Lanthionine-Containing Peptides on Solid Phase ....

Challenges and Innovations

Despite the advances, challenges persist in the solid-phase synthesis of lanthionine-containing peptides.the present invention relates to a procedure forsolidphase peptide synthesis (SPPS), following a linear or convergent strategy, wherein the peptides contain ... Steric hindrance around the reactive sites can impede efficient coupling or cyclization. However, researchers have developed all-solid-phase approaches that are applicable to lanthionine formation in less sterically hindered peptides.

The ability to perform solid-phase synthesis of sulfamidate-containing peptides followed by late-stage intramolecular cyclization represents another innovative approach. This method offers a different route to generating the thioether linkage and has been applied to the synthesis of fluorescent lanthipeptide compounds.

Furthermore, the development of green and efficient methods for preparing lanthionine peptides is an ongoing area of research. One such advancement is a highly chemoselective and stereo-controlled method for preparing lanthionine peptides by S-alkylation with substituted cyclic sulfamidates.Synthesis and Conformational Studies of the Lipid II- ... This approach has enhanced the efficiency and environmental friendliness of the synthesis of lanthionine peptides.Lanthionine - an overview

Applications and Future Directions

The robust methodologies developed for solid-phase synthesis of lanthionine-containing peptides have paved the way for numerous applications.作者：S De Luca·2018·被引用次数：17—A one-pot, high-yield procedure forsynthesizing lanthionine-containing peptideswas developed. It relies on the S-alkylation of ... These include:

* Antimicrobial Agents: Many lantibiotics exhibit potent antibacterial properties, making them attractive leads for developing new antibiotics to combat drug-resistant pathogens.

* Biomedical Research: Synthesized lanthionine-containing peptides are invaluable tools for studying their biological mechanisms of action, such as the molecular recognition of Lipid II by LantibioticsSynthesis of Lanthionine-Containing Peptides on Solid Phase ....

* Drug Discovery: These peptides can be modified to create analogues with improved pharmacokinetic properties or novel therapeutic applications, like solid-phase synthesis of new Trp(Nps)-containing dipeptide derivatives acting as TRPV1 channel blockers.Solid-Phase Peptide Synthesis of Analogues of the N- ...

The continuous refinement of solid-phase peptide synthesis techniques, coupled with the exploration of novel protecting group strategies and coupling chemistries, promises further advancements in the field. The ability to efficiently and reliably synthesize these complex molecules will undoubtedly lead to the discovery of new bioactive peptides and expand our understanding of peptide biochemistry. The solid phase remains a critical platform for this innovation, enabling the construction of intricate molecular architectures with unprecedented accuracy.