total synthesis mersacidin solid-phase peptide synthesis Total synthesis - total-synthesis-mersacidin-solid-phase-peptide Total synthesis The Total Synthesis of Mersacidin via Solid-Phase Peptide Synthesis: A Deep Dive

nexgen-peptides-shop Mersacidin, a potent antimicrobial peptide belonging to the lantibiotic class, has garnered significant attention due to its broad-spectrum activity against Gram-positive bacteria作者：H Liu·2010·被引用次数：1—Synthesisof N-terminal pentapeptides. 42. 2.2.I.e.Solid Phase Peptide Synthesisof oxa-lacticin 3147 A2 (45). 44. 2.2.l.d. Biological testing of oxa-lacticin .... Its unique structure, characterized by the presence of lanthionine bridges, presents a formidable challenge for chemical synthesis. However, advancements in solid-phase peptide synthesis (SPPS) have paved the way for the total synthesis of mersacidin and its analogues, enabling comprehensive studies into their structure-activity relationships and potential therapeutic applications. This article delves into the intricate process of mersacidin total synthesis using solid-phase peptide synthesis, exploring the key methodologies, challenges, and the significance of this approach.All the samples were prepared in an analogous manner first dissolving peptide ...Solid-phase peptide synthesis, a practical approach; IRL Press: Oxford, 1989.

Understanding Mersacidin: A Lantibiotic Powerhouse

Mersacidin is a 20-amino acid peptide produced by *Bacillus* species. As a lantibiotic, its defining feature is the presence of thioether cross-links formed between cysteine residues and dehydroamino acids, such as dehydroalanine. These unique post-translational modifications contribute to the peptide's structural rigidity and enhanced antimicrobial potencyOrthogonally Protected Lanthionines: Synthesis and Use .... Mersacidin primarily targets the bacterial cell wall biosynthesis pathway by interacting with lipid II, a crucial precursor molecule. This disruption leads to cell lysis and bacterial death作者：SM Rowe·2021·被引用次数：38—In typicalsolid-phase peptide synthesis(SPPS) strategies, only one linkage to a solid-support is provided through the C-terminus of the .... The exploration of mersacidin and similar antimicrobial peptides is particularly relevant in the face of rising antibiotic resistance.

The Power of Solid-Phase Peptide Synthesis (SPPS)

Solid-phase peptide synthesis (SPPS), pioneered by R. Bruce Merrifield, revolutionized peptide chemistry.Large-Scale Synthesis of Peptides This technique involves anchoring the C-terminal amino acid of the desired peptide to an insoluble polymer resin.Solid-Phase Peptide Synthesis Subsequent amino acids are then sequentially added to the growing peptide chain, with each step involving deprotection of the N-terminus, coupling of the next protected amino acid, and washing away excess reagents. The solid support facilitates easy separation of the product from unreacted materials and byproducts through simple filtration and washingSynthesis, antimicrobial activity, and mechanistic studies of ....

For the total synthesis of complex peptides like mersacidin, SPPS offers several advantages:

* Efficiency: The ability to wash away excess reagents at each step drives reactions to completion, leading to higher yields.

* Automation: SPPS is amenable to automation, allowing for the rapid synthesis of numerous peptides and libraries of analogues.

* Simplified Purification: The solid support significantly simplifies the purification process compared to solution-phase methods.

* Handling of Intermediates: The immobilized nature of the growing peptide chain makes handling and purification of intermediates more manageable.

Total Synthesis of Mersacidin: A Step-by-Step Approach

The total synthesis of mersacidin via solid-phase peptide synthesis typically involves a series of carefully orchestrated steps, often employing the Fmoc/tBu (9-fluorenylmethoxycarbonyl/tert-butyl) strategy. This widely adopted method utilizes acid-labile tert-butyl based protecting groups for side chains and base-labile Fmoc for the N-terminus.

1. Resin Loading: The synthesis begins by attaching the first amino acid (usually the C-terminal one) to a suitable solid support resin. Various resins are available, such as Wang resin or Rink amide resin, depending on the desired C-terminus of the final peptide.

2. Deprotection: The N-terminal protecting group (Fmoc) is removed using a mild base, typically piperidine.Epimerisation in Peptide Synthesis This exposes the free amine for the next coupling step.

3. Amino Acid Coupling: The next Fmoc-protected amino acid, activated with a coupling reagent (e.g., HBTU, HATU, DIC/HOBt), is added to the resinAI. The research details thetotal synthesisof the lantibiotic lactocin S, a naturalpeptidefrom Lactobacillus sakei, throughsolid-phase peptidecyclizations .... The activated carboxyl group of the incoming amino acid reacts with the free amine on the growing peptide chain, forming a new peptide bond.

4. Washing: After each deprotection and coupling step, the resin is thoroughly washed with appropriate solvents to remove excess reagents and byproducts. This is a critical step in solid-phase peptide synthesis for ensuring the purity of the final productAll the samples were prepared in an analogous manner first dissolving peptide ...Solid-phase peptide synthesis, a practical approach; IRL Press: Oxford, 1989..

5. Cyclization and Lanthionine Formation: A key challenge in mersacidin total synthesis is the formation of the characteristic lanthionine rings. This often requires specific strategies, including the use of modified amino acids or post-synthetic cyclization reactions.Then typically, all the protecting groups are removed and thepeptideresin is washed, and thepeptideis cleaved from the resin. Figure 1 – GeneralSolid Phase... The formation of these thioether bridges can be achieved through various chemical methods, often involving the dehydration of serine or threonine residues to form dehydroamino acids, followed by conjugate addition of cysteine thiols. The precise sequence and conditions for these modifications are crucial for successful total synthesis.

6. Cleavage and Deprotection: Once the full amino acid sequence is assembled and modified, the peptide is cleaved from the solid support resin using a strong acid cocktail (e.g., trifluoroacetic acid, TFA)Orthogonally Protected Lanthionines: Synthesis and Use .... This cocktail also simultaneously removes all the tert-butyl based side-chain protecting groups. The choice of cleavage cocktail is critical to avoid side reactions and ensure the integrity of the peptide作者：I Coin·2007·被引用次数：881—Stir gently for 30 s and wait for 5 min. Repeat five times (totalreaction time is. 30 min, coupling step), and then remove the solvent by ....

7. Purification and Characterization: The crude peptide obtained after cleavage is then purified, typically using reverse-phase high-performance liquid chromatography (RP-HPLC). The purified mersacidin is then characterized using techniques such as mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy to confirm its identity and purity.

Challenges and Innovations in Mersacidin Synthesis

Despite the power of SPPS, the total synthesis of mersacidin is not without its challenges:

* Lanthionine Ring Formation: The precise regioselective and stereoselective formation of multiple lanthionine rings remains a significant hurdle. Developing efficient and reliable methods for these cyclizations is an ongoing area of research.作者：H Liu·2010·被引用次数：1—Synthesisof N-terminal pentapeptides. 42. 2.2.I.e.Solid Phase Peptide Synthesisof oxa-lacticin 3147 A2 (45). 44. 2.2.l.d. Biological testing of oxa-lacticin ...

* Aggregation: As the peptide chain grows on the solid support, aggregation can occur, leading to incomplete reactions and reduced yields.[41,42] We have developed very effectivesolid-phase peptidesynthesis methodology which we and others have appliedtothesynthesisof individual rings of ... Careful selection of solvents and coupling reagents can mitigate this.

* Racemization: During coupling steps, epimerization of amino acid residues can occur, leading to undesired stereoisomers. Optimizing coupling conditions and using specific additives can minimize this.

* Scale-up: While SPPS is efficient for laboratory-scale synthesis, scaling up the process for industrial production can be challenging and requires specialized equipment and optimized protocols作者：L Lepsa·2000·被引用次数：271—2 Illustration of the development approach for Atosiban drug substance, utilizing a common intermediate for solution- andsolid-phasesyntheses. 236. Andersson ....

Researchers are continuously developing innovative strategies to overcome these limitations.synthesis and biological - studies of lanthionine derivatives This includes the use of novel resins, improved coupling reagents, orthogonal protecting group strategies, and the integration of microwave-assisted synthesis to accelerate reaction times. The synthesis of analogues of mersacidin is also a key focus, allowing for the exploration of how structural modifications impact antimicrobial activity and pharmacokinetic properties.

The Significance of Total Synthesis

The ability to perform the total synthesis of mersacidin using solid-phase peptide synthesis has profound implications:

* Structure-Activity Relationship (SAR) Studies: Synthesizing various mersacidin analogues with modifications at specific positions allows researchers to understand which structural features are essential for its antimicrobial activity.Full-text available. Apr 2024; ANGEW CHEM INT EDIT · Hongxiang Wu · Zhenquan Sun · Xuechen Li. Althoughsolid‐phase peptide synthesis... This knowledge is invaluable for designing more potent and selective therapeutic agents.

* Mechanistic Investigations: Having pure, synthetically derived mersacidin enables detailed studies into its mechanism of action at a molecular level.

* Drug Development: The total synthesis provides a reliable route for producing sufficient quantities of mersacidin and its derivatives for preclinical and clinical trials, paving the way for its potential use as a novel antibiotic.

* Access to Difficult-to-Obtain Peptides: SPPS allows for the synthesis of peptides that may be difficult or impossible to isolate from their natural sources in sufficient quantitiesMersacidin - an overview.

In conclusion, the total synthesis of mersacidin through solid-phase peptide synthesis represents a significant achievement in peptide chemistryUniversity of Alberta. This powerful methodology, coupled with ongoing innovation, continues to unlock the potential of this remarkable lantibiotic, offering promising avenues for combating bacterial infections and advancing our understanding of antimicrobial drug design.作者：EL Ongey·2016·被引用次数：137—...solid-phase peptide synthesis;. VRE: vancomycin resistant Enterococci. ...Total synthesisof peptide antibiotic nisin. Tetrahe- dron Lett ... The ongoing research in peptide synthesis and the exploration of related compounds like malacidin highlight the dynamic nature of this fieldSynthesis Notes.