Synthesis of Second-Generation Analogs of Temporin-SHa Peptide Having Broad-Spectrum Antibacterial and Anticancer Effects

Antibiotics, Journal Year: 2024, Volume and Issue: 13(8), P. 758 - 758

Published: Aug. 11, 2024

Antimicrobial peptides (AMPs) are a promising class of therapeutic alternatives with broad-spectrum activity against resistant pathogens. Small AMPs like temporin-SHa (1) and its first-generation analog [G10a]-SHa (2) possess notable efficacy Gram-positive Gram-negative bacteria. In an effort to further improve this antimicrobial activity, second-generation analogs 1 were synthesised by replacing the natural glycine residue at position-10 parent molecule atypical amino acids, such as D-Phenylalanine, D-Tyrosine (2-Naphthyl)-D-alanine, study effect hydrophobicity on efficacy. The resultant (3–6) emerged antibacterial agents. Notably, [G10K]-SHa (4), having lysine substitution, demonstrated 4-fold increase in (Enterobacter cloacae DSM 30054) (Enterococcus faecalis 2570) bacteria relative peptide (1). Among all analogs, [G10f]-SHa (3), featuring D-Phe showed most potent anticancer lung cancer (A549), skin (MNT-1), prostate (PC-3), pancreatic (MiaPaCa-2) breast (MCF-7) cells, achieving IC50 value range 3.6–6.8 µM; however, it was also found be cytotoxic normal cell lines compared (4). Peptide 4 possessed good but less 3. These findings underscore potential especially 4, leads develop new

Language: Английский

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Sustainable Approaches in Solid-phase Peptide Synthesis (SPPS)

Royal Society of Chemistry eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 50 - 84

Published: Oct. 18, 2024

Solid-phase peptide synthesis (SPPS) is a ubiquitous methodology for making peptides from R&D to manufacturing plant, not least in the context of using and peptidometics as pharmaceuticals. Nevertheless, SPPS has long been plagued by its reliance on large amounts hazardous materials such dimethylformamide solvent trifluoroacetic acid cleavage reagent. Consequently, with methods producing sustainable manner being high demand, numerous reports covering various aspects greening have appeared recent years. In this chapter, an integrated overview state-of-the-art field presented, highlighting advances within entire workflow starting amino coupling cycle cleaving off polymer support. Greener assembly complex waste minimization tactics are also delineated, together discussion adoption practice, scale-up, procurement, costs intellectual property key considerations attaining truly SPPS. Finally, perspective future directions towards elevating versatile, platform provided.

Language: Английский

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A Sustainable Chemo-Enzymatic Approach to the Synthesis of Liraglutide

ACS Sustainable Chemistry & Engineering, Journal Year: 2024, Volume and Issue: 12(45), P. 16791 - 16799

Published: Nov. 1, 2024

The development of green approaches to peptide synthesis is essential, as peptides are gaining prominence in the pharmaceutical market. Traditional methods often involve harmful solvents and high energy use, prompting a shift toward sustainable eco-friendly alternatives. Liraglutide, GLP-1 analogue used treatment obesity type-2 diabetes, has been synthesized through hybrid chemo-enzymatic approach (CEPS), taking advantage solvent mixtures fragments selectivity ligase enzyme for their coupling. This method offers great advantages both quality upstream wastes reduction volumes downstream purification, together with purity target liraglutide.

Language: Английский

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Optimizing Industrial Solid-Phase Peptide Synthesis: Integration of Raman Spectroscopy as Process Analytical Technology

Organic Process Research & Development, Journal Year: 2024, Volume and Issue: 28(12), P. 4501 - 4512

Published: Dec. 10, 2024

Peptide therapeutics have exploded in popularity recent years, motivating the need for advanced manufacturing methods which can be applied across solid-phase peptide synthesis (SPPS) process. The Food and Drug Administration's Process Analytical Technology (PAT) initiative offers a platform to implement improve efficiency understanding of pharmaceutical processes shows great promise application toward industrial SPPS. In this work, Raman spectroscopy was used as main PAT tool on-line real-time monitoring entire SPPS process, from Fmoc removal, coupling, through extensive solvent-washing steps. is rapid, specific, nondestructive technique that provide rich information solvent use save process time. Specifically, work reports on development amino acid coupling during stage residual piperidine concentration post-deprotection washing SPPS, help reduce better understand reaction its time frame. We show significant reduction possible by employing along with partial least squares model predict real continuous wash. addition, greater kinetics could lead improvements total

Language: Английский

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Advancing Sustainable Peptide Synthesis by Solvent Quality Control: Understanding and Mitigating Hydroperoxide in 1-Butyl-2-pyrrolidinone (NBP)

Organic Process Research & Development, Journal Year: 2024, Volume and Issue: 28(8), P. 3347 - 3367

Published: July 25, 2024

While numerous studies aimed at producing peptides in a sustainable manner have recently been reported, the impact of quality starting materials on sustainability peptide synthesis has less investigated. Here we report that NBP, greener dipolar aprotic solvent suitable for use SPPS, readily undergoes air oxidation to corresponding hydroperoxide (NBP-OOH), which adversely affects oxidation-sensitive amino acids and peptides. Air, light, elevated temperatures, common reagents such as DIC accelerated rate NBP oxidation. LC-HRMS analyses revealed air-induced degradation proceeds via different mechanism than previously elucidated closely related NMP while GC–MS containing NBP-OOH showed standard GC-based analytical methods are unsuitable detection, warranting implementation improved analyses. Assessment NBP-OOH-induced Met, Trp, Cys, Tyr breakdown not only degrades all these oxidation-prone substrates, but it was also discovered DITU, reported suppress N-oxyl radical-induced breakdown, constitutes an efficient suppressant hydroperoxide-induced degradation. Studies aerial additional solvents DMSO DMPU former is stable does cause oxidation, latter oxidized extensively upon exposure substrates significant extent. On other hand, bubbling DMSO, proved unexpected positive effect stability α-amino-bound Fmoc group, finding may be leveraged minimize premature loss during synthesis. Overall, our understanding mitigating formation illustrate importance thorough assessment development synthetic methods.

Language: Английский

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Green Metrics for a Sustainable Approach in Iterative Processes

Royal Society of Chemistry eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 9 - 22

Published: Oct. 18, 2024

This chapter focuses on iterative processes of peptides and oligonucleotides (TIDES) with critical evaluation the available green metrics developed for small molecules. Chemical syntheses TIDES involve a large number basic reaction sequences, some metrics, such as atom economy (AE) ideality factor, become useless. The key that allow rapid comparisons different or technologies are mass efficiency (RME), process intensity (PMI) recovery (PMIr). “carbon footprint” is useful metric overall plant/business but not technologies.

Language: Английский

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