solid-phase peptide synthesis total synthesis lantibiotic phase peptide - solid-phase-peptide-synthesis-of-lanthipeptides total synthesis

is-ghk-cu-a-peptide The total synthesis of lantibiotic peptides, particularly through solid-phase peptide synthesis (SPPS), represents a significant advancement in medicinal chemistry and natural product research. Lantibiotics are a class of antimicrobial peptides characterized by their unique post-translational modifications, including the presence of the non-proteinogenic amino acid lanthionine. These complex structures, while naturally occurring, present considerable challenges for de novo chemical synthesis. Solid-phase peptide synthesis offers a robust and versatile platform for constructing these intricate molecules, enabling the creation of novel analogues and the detailed study of their biological functions.

The Challenge and Promise of Lantibiotic Synthesis

Lantibiotics, derived from bacterial sources, are known for their potent antimicrobial activity, often targeting Gram-positive bacteria, including drug-resistant strains. Their complex architecture, featuring thioether bridges and dehydroamino acids, makes them difficult to synthesize using traditional solution-phase methods. Total synthesis, the complete construction of a molecule from simple starting materials, is crucial for several reasons: it allows for the production of compounds that may be scarce in nature, facilitates the creation of modified analogues with potentially improved properties (e.g., enhanced potency, altered spectrum of activity, or better pharmacokinetic profiles), and provides a means to confirm proposed natural product structures.

Solid-phase peptide synthesis has emerged as a cornerstone technique for tackling the complexity of lantibiotics.作者：EL Ongey·2016·被引用次数：138—Total synthesisof peptideantibioticnisin. Tetrahedron Lett ... Thesolid phasesupportedpeptide synthesisof analogues of thelantibioticlactocin S. This method involves anchoring the growing peptide chain to an insoluble solid support, allowing for the sequential addition of amino acids and subsequent purification through simple washing steps. This approach simplifies the process and often leads to higher yields compared to solution-phase synthesis, especially for longer or more complex peptide sequences作者：SMK McKinnie·2012·被引用次数：20—Four analogues of lactocin S, an antimicrobiallantibiotic peptideproduced by Lactobacillus sakei L45, have been generated usingsolid-phase peptide....

Solid-Phase Peptide Synthesis (SPPS) for Lantibiotics

The application of SPPS to lantibiotic synthesis typically involves the use of protecting group strategies, most commonly the 9-fluorenylmethoxycarbonyl (Fmoc) strategy作者：PJ Knerr·2013·被引用次数：70—(32) Therefore, we drew upon previoustotalsyntheses oflantibioticsvia 9-fluorenylmethoxycarbonyl-basedsolid-phase peptide synthesis(Fmoc-SPPS) (14, 22) to .... This method allows for the stepwise elongation of the peptide chain from the C-terminus to the N-terminus. Key aspects of SPPS in this context include:

* Resin Selection: The choice of solid support (resin) and linker is critical for the success of the synthesis, influencing cleavage conditions and the final product's integrity.

* Amino Acid Protection: Orthogonal protecting groups are essential to selectively deprotect reactive side chains and the N-terminus for peptide bond formation, while preventing unwanted side reactions.

* Lanthionine Incorporation: The synthesis of lanthionine and its derivatives, often in protected forms, is a specialized step that needs to be integrated into the SPPS workflow.Chemical and chemoenzymatic syntheses of lantibiotics and ...

* Cyclization and Modification: After the linear peptide is assembled on the resin, cyclization reactions (e.g., thioether bond formation) and other post-translational modifications are performed, either on-resin or after cleavage.

Researchers have successfully employed SPPS to synthesize various lantibiotics and their analogues, including lactocin S, lacticin 481, and others. This has not only validated the synthetic routes but also provided access to these valuable compounds for further biological evaluation and potential therapeutic development.Synthesis of Some Analogues of Polymyxin E1 Antibiotic ...

Challenges and Future Directions

Despite the advancements, the total synthesis of lantibiotics via SPPS remains a challenging endeavor作者：K Manzor·2017·被引用次数：9—Solid-phase peptide synthesisof five A-ring analogues of thelantibioticnisin. ·Solid-phase synthesisof a nisin A-ring analogue containing a thioamide link.. Issues such as incomplete coupling, side reactions, and difficulties in achieving the correct stereochemistry can arise. The unique structural features of lantibiotics, such as thioether rings, require specialized chemical strategies that must be compatible with the SPPS workflow.

Future research in this area is likely to focus on developing more efficient and robust synthetic methodologies, exploring novel protecting group strategies, and utilizing automated synthesis platforms to accelerate the production of lantibiotic libraries. The ability to synthesize these complex peptides is vital for unlocking their full therapeutic potential and for gaining deeper insights into their mechanisms of action. As our understanding of lantibiotic biosynthesis and structure-activity relationships grows, solid-phase peptide synthesis will continue to be an indispensable tool in this exciting field of chemical synthesis and drug discoverySolid Supported Chemical Syntheses of Both Components of ....