“CLipP”ing on lipids to generate antibacterial lipopeptides

Yim, V.; Kavianinia, Iman; Knottenbelt, Melanie K.; Ferguson, Scott; Cook, Gregory M.; Swift, Simon; Chakraborty, Aruna; Allison, Jane R.; Cameron, Alan J.; Harris, Paul W. R.; Brimble, Margaret A.

doi:10.1039/d0sc01814g

Cited by 17 publications

(17 citation statements)

References 22 publications

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“…Chem. Sci.20201157595765 . This work demonstrates the utility of radical initiated thiol–ene chemistry in the production of antimicrobial lipopeptides.…”

Section: Key Referencesmentioning

confidence: 79%

“…Inspired by this work, the Brimble group sought to further probe the SAR of battacin through generation of a library of linear analogues bearing various lipids installed using CLipPA S -lipidation (Scheme ). To this end, Fmoc-strategy SPPS was used to construct two scaffolds with either 3-mercaptoproprionate (MPA) or an l -Cys residue at the N-terminus. Following resin cleavage, CLipPA-enabled lipidation furnished the series of 14 analogues ( 36 – 49 ) after HPLC purification.…”

Section: Antibiotics Against Gram-negative Bacterial Infectionsmentioning

confidence: 99%

“…The wide structural diversity found in NRPs has provided chemists with ample opportunity for total synthesis and medicinal chemistry campaigns. − Moreover, recent expansions to the chemical toolbox have allowed for a wealth of new structures to be explored in structure–activity relationship (SAR) studies. CLipPA (cysteine lipidation on a peptide or amino acid) technology has emerged as a powerful tool for the facile lipidation of peptides bearing a free thiol. ,− The lipidation takes place via a radical initiated thiol–ene reaction between the peptidyl free thiol and the terminal sp 2 carbon of a fatty acid vinyl ester. Importantly, vinyl esters are readily obtainable, and the easy workup of the reaction allows for rapid generation of lipopeptide analogues bearing various lipids.…”

Section: Introductionmentioning

confidence: 99%

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Discovery, Synthesis, and Optimization of Peptide-Based Antibiotics

et al. 2021

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Conspectus The rise of multidrug resistant bacteria has significantly compromised our supply of antibiotics and poses an alarming medical and economic threat to society. To combat this problem, it is imperative that new antibiotics and treatment modalities be developed, especially those toward which bacteria are less capable of developing resistance. Peptide natural products stand as promising candidates to meet this need as bacterial resistance is typically slow in response to their unique modes of action. They also have additional benefits including favorable modulation of host immune responses and often possess broad-spectrum activity against notoriously treatment resistant bacterial biofilms. Moreover, nature has provided a wealth of peptide-based natural products from a range of sources, including bacteria and fungi, which can be hijacked in order to combat more dangerous clinically relevant infections. This Account highlights recent advances in the total synthesis and development of a range of peptide-based natural product antibiotics and details the medicinal chemistry approaches used to optimize their activity. In the context of antibiotics with potential to treat Gram-positive bacterial infections, this Account covers the synthesis and optimization of the natural products daptomycin, glycocin F, and alamethicin. In particular, the reported synthesis of daptomycin highlights the utility of on-resin ozonolysis for accessing a key kynurenine residue from the canonical amino acid tryptophan. Furthermore, the investigation into glycocin F analogues uncovered a potent lead compound against Lactobacillus plantarum that bears a non-native thioacetal linkage to a N-acetyl-d-glucosamine (GlcNAc) sugar, which is otherwise O-linked in its native form. For mycobacterial infections, this Account covers the synthesis and optimization of teixobactin, callyaerin A, lassomycin, and trichoderin A. The synthesis of callyaerin A, in particular, highlighted the importance of a (Z)-2,3-diaminoacrylamide motif for antimicrobial activity against Mycobacterium tuberculosis, while the synthesis of trichoderin A highlighted the importance of (R)-stereoconfiguration in a key 2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid (AHMOD) residue. Lastly, this Account covers lipopeptide antibiotics bearing activity toward Gram-negative bacterial infections, namely, battacin and paenipeptin C. In both cases, optimization of the N-terminal lipid tails led to the identification of analogues with potent activity toward Escherichia coli and Pseudomonas aeruginosa.

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“…Chem. Sci.20201157595765 . This work demonstrates the utility of radical initiated thiol–ene chemistry in the production of antimicrobial lipopeptides.…”

Section: Key Referencesmentioning

confidence: 79%

Section: Antibiotics Against Gram-negative Bacterial Infectionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Discovery, Synthesis, and Optimization of Peptide-Based Antibiotics

et al. 2021

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“…In their recent studies utilizing the CLipPA methodology, Yim et al synthesized a number of linear Battacin analogs with varying lipid chains (Yim et al, 2020a ). The previously developed system utilizing DPAP, TIPS and t NonSH in NMP afforded lipopeptides in yields ranging from 1 to 32%, with >94% purity via either an N -terminal Cys or 3-mercaptopropionate (MPA) handle.…”

Section: Amino Acid and Peptide Lipidationmentioning

confidence: 99%

Applications of Thiol-Ene Chemistry for Peptide Science

Nolan

Scanlan

2020

Front. Chem.

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Radical thiol-ene chemistry has been demonstrated for a range of applications in peptide science, including macrocyclization, glycosylation and lipidation amongst a myriad of others. The thiol-ene reaction offers a number of advantages in this area, primarily those characteristic of “click” reactions. This provides a chemical approach to peptide modification that is compatible with aqueous conditions with high orthogonality and functional group tolerance. Additionally, the use of a chemical approach for peptide modification affords homogeneous peptides, compared to heterogeneous mixtures often obtained through biological methods. In addition to peptide modification, thiol-ene chemistry has been applied in novel approaches to biological studies through synthesis of mimetics and use in development of probes. This review will cover the range of applications of the radical-mediated thiol-ene reaction in peptide and protein science.

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“…Articial modications such as lipidation, cyclization and stereoisomerisation are oen required to overcome the shortcomings inherent to peptides, including their natural hydrophilicity, structural instability and proteolytic vulnerability. [23][24][25][26][27][28][29] Meanwhile, a notable class of membrane-targeting cyclometalated iridium(III) complexes, have gained increasing attention because of their biomolecular reactivities and potent anticancer activities of novel mechanisms. [30][31][32][33][34][35][36][37] In this work, these two classes of membrane active compounds are bioconjugated to remove their respective disadvantages; for example, the iridium complex contributes to the peptide structural stability and enables luminescence-based analysis, whereas peptides endow the iridium complex with a suitable solubility.…”

Section: Introductionmentioning

confidence: 99%