total synthesis of lacticin 481 solid-phase peptide synthesis peptides - tr20-peptide Lacticin 481

total-synthesis-of-haloduracin-solid-phase-peptide-synthesis The total synthesis of lacticin 481 through solid-phase peptide synthesis (SPPS) represents a significant achievement in the chemical construction of complex natural products. Lacticin 481, a lantibiotic, is characterized by its unique post-translational modifications, including lanthionine and methyllanthionine cross-links, which are crucial for its antimicrobial activityChemical Synthesis of the Lantibiotic Lacticin 481 Reveals the .... Achieving its total synthesis requires sophisticated strategies within solid-phase methodologies to assemble the peptide backbone and introduce these intricate structural features.

Challenges in Lacticin 481 Total Synthesis

The primary challenge in the total synthesis of lacticin 481 lies in the precise incorporation and stereochemical control of non-proteinogenic amino acids and the formation of thioether bridges.Full solid-phase total synthesis of macrocyclic natural ... Traditional SPPS methods, while effective for linear peptides, need adaptation to handle the cyclization and cross-linking characteristic of lantibiotics. Researchers have leveraged advanced SPPS techniques, often employing the Fmoc (9-fluorenylmethoxycarbonyl) strategy, to build the peptide chain on a solid support.ChemicalSynthesisof the LantibioticLacticin 481Reveals the Importance of Lanthionine Stereochemistry · Thesynthesisof active and stable diaminopimelate ... This approach allows for iterative coupling of protected amino acids and subsequent cleavage from the resin.

A critical aspect of lacticin 481 synthesis involves the introduction of lanthionine (Lan) and methyllanthionine (MeLan) residues.作者：B Mothia·2012·被引用次数：2—Thesynthesisof two sets of different orthogonally protected lanthionine ready for incorporation intosolid phase peptide synthesisto form cyclised peptides ... These modified amino acids are formed via nucleophilic attack of cysteine thiols onto dehydroalanine or dehydrobutyrine residues. The stereochemistry of these cross-links can significantly impact the peptide's biological activity, making their controlled formation a key synthetic goal. Solid-phase synthesis provides a platform to incorporate pre-formed, orthogonally protected Lan and MeLan building blocks, or to facilitate their in-situ formation during the synthesisSynthesis of the lantibiotic lactocin S using peptide ....

Solid-Phase Peptide Synthesis Strategies

The application of solid-phase peptide synthesis for complex peptides like lacticin 481 has been refined over the years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 .... Strategies often involve:

* Fmoc-Based SPPS: This is a widely adopted method due to the mild conditions required for Fmoc deprotection (using piperidine), which are compatible with many sensitive functional groups and peptide structures.

* Orthogonal Protection: Employing protecting groups that can be removed independently under different conditions is vital for selectively modifying specific amino acid side chains or enabling cyclization reactions. This is particularly important for managing the reactive thiols of cysteine residues and the formation of thioether bonds.

* Incorporation of Modified Amino Acids: Synthesizing or acquiring orthogonally protected lanthionine and methyllanthionine building blocks is essential.Full solid-phase total synthesis of macrocyclic natural ... These units are then coupled to the growing peptide chain on the solid support.Lanthipeptides: chemical synthesis versus in vivo biosynthesis ...

* Cyclization and Cleavage: After assembling the linear peptide precursor on the resin, cyclization reactions are performed, often involving the formation of thioether bridges. Subsequent cleavage from the solid support and final deprotection steps yield the target peptide.

Research has demonstrated that solid-supported chemical synthesis enables the total synthesis of lacticin 481 and its analogues, allowing for the exploration of structure-activity relationships by varying the stereochemical configurations of cross-links. This synthetic capability is crucial for understanding how these modifications contribute to the lantibiotic's potency and spectrum of activity.

Significance and Future Directions

The successful total synthesis of lacticin 481 via SPPS not only validates chemical methodologies but also provides access to the compound and its derivatives for further biological evaluation作者：H Itoh·2019·被引用次数：18—Lacticin 481(14, Fig. 7), a tricyclic lantibiotic consisting of. 27 amino acid residues,40 is produced by Lactococcus lactis subsp. lactis.41 .... This is important because natural production of such peptides can be low, and modifications are often needed to enhance their therapeutic properties, such as stability or efficacy against resistant strains.This review focuses on four-dimensionally orthogonal protective group strategies for thefull solid-phase synthesisof macrocyclicpeptideswith branched chains ...

Future work in this area may focus on developing more efficient and scalable SPPS strategies for lantibiotics, potentially incorporating chemoenzymatic approaches or exploring novel solid supports and coupling reagentsThe methodology is complementary tosolid-phase peptide synthesis(SPPS) and may be particularly suited for laboratories that are not experts in SPPS. Genes .... The ability to synthesize these complex molecules synthetically is critical for advancing their potential applications as antimicrobial agents in medicine and agriculture.Engineering Dehydro Amino Acids and Thioethers into ...