Synthesis and evaluation of novel macrocyclic antifungal peptides

Mulder, Monique P. C.; Kruijtzer, John A. W.; Breukink, Eefjan; Kemmink, Johan; Pieters, Roland J.; Liskamp, Rob M. J.

doi:10.1016/j.bmc.2011.08.034

Cited by 15 publications

(17 citation statements)

References 40 publications

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“…Another aspect that can be crucial to antimicrobial activity of cyclic ultrashort cationic lipopeptides is ring size. It was found that the ring size of cyclized antimicrobial peptides and lipopeptides (polymyxin B, echinocandins) was an essential factor that can affect biological activity [ 87 , 88 , 89 , 90 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of Disulfide Cyclization of Ultrashort Cationic Lipopeptides on Antimicrobial Activity and Cytotoxicity

Neubauer

Jaśkiewicz

Sikorska

et al. 2020

IJMS

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Ultrashort cationic lipopeptides (USCLs) are considered to be a promising class of antimicrobials with high activity against a broad-spectrum of microorganisms. However, the majority of these compounds are characterized by significant toxicity toward human cells, which hinders their potential application. To overcome those limitations, several approaches have been advanced. One of these is disulfide cyclization that has been shown to improve drug-like characteristics of peptides. In this article the effect of disulfide cyclization of the polar head of N-palmitoylated USCLs on in vitro biological activity has been studied. Lipopeptides used in this study consisted of three or four basic amino acids (lysine and arginine) and cystine in a cyclic peptide. In general, disulfide cyclization of the lipopeptides resulted in peptides with reduced cytotoxicity. Disulfide-cyclized USCLs exhibited improved selectivity between Candida sp., Gram-positive strains and normal cells in contrast to their linear counterparts. Interactions between selected USCLs and membranes were studied by molecular dynamics simulations using a coarse-grained force field. Moreover, membrane permeabilization properties and kinetics were examined. Fluorescence and transmission electron microscopy revealed damage to Candida cell membrane and organelles. Concluding, USCLs are strong membrane disruptors and disulfide cyclization of polar head can have a beneficial effect on its in vitro selectivity between Candida sp. and normal human cells.

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Section: Discussionmentioning

confidence: 99%

Effect of Disulfide Cyclization of Ultrashort Cationic Lipopeptides on Antimicrobial Activity and Cytotoxicity

Neubauer

Jaśkiewicz

Sikorska

et al. 2020

IJMS

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“…Mulder et al [179] designed caspofungin mimic 142 in which the alkene moiety formed an alternative constraint for the hemiaminal, since the latter is known to be unstable at pH > 7. Precursor peptide 143 was synthesized on the solid support following Fmoc/ t Bu SPPS protocols.…”

Section: Rcm For the Synthesis Of Bioactive Peptides And Peptidomimeticsmentioning

confidence: 99%

“…As the fifth example [179], RCM was applied to constrain and simplify caspofungin (141) as an antifungal peptide that belongs to the class of echinocandins that act by inhibiting the β-(1,3)-D-glucan synthase complex [180].…”

Section: Rcm For the Synthesis Of Bioactive Peptides And Peptidomimeticsmentioning

confidence: 99%

Synthesis of Cyclic Peptides and Peptidomimetics by Metathesis Reactions

Rijkers

2015

Topics in Heterocyclic Chemistry

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This review surveys developments in the field of ring-closing metathesis and cross-metathesis reactions applied to the synthesis of constrained amino acids, peptides, and peptidomimetics. Examples, in which metathesis is used as one of the synthetic tools to arrive at the desired peptide molecules as well as examples that describe in-depth optimized metathesis protocols, will be discussed. Currently, metathesis reactions are well-accepted synthetic tools within the field of peptide chemistry and provide peptides unprecedented properties like conformational, metabolic, and chemical stability and improved bioactivity.

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“…On‐resin microwave‐assisted RCM ring closure using a common Pro residue having a 3‐(4‐pentenyloxy) group and the appropriate length N (τ)–alkenyl group was possible for the 20, 22, and 24‐member macrocycles ( 8b – 8d , respectively, Figure ). Microwave irradiation can decrease reaction times, enhance catalyst performance and improve overall yields of RCM reactions . Typically, these reactions are conducted in a solvent combination of CH 2 Cl 2 : dimethylformamide (DMF) (10 : 1) using 2nd Generation Grubbs or Hoveyda‐Grubbs catalyst.…”

Section: Resultsmentioning

confidence: 99%

Neighbor‐directed histidine N (τ)–alkylation: A route to imidazolium‐containing phosphopeptide macrocycles

et al. 2015

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Our recently discovered, selective, on-resin route to N(τ)-alkylated imidazolium-containing histidine residues affords new strategies for peptide mimetic design. In our current work, we demonstrate the use of this chemistry to prepare a series of macrocyclic phosphopeptides, in which imidazolium groups serve as ring-forming junctions. Interestingly, these cationic moieties subsequently serve to charge-mask the phosphoamino acid group that directed their formation. Neighbor-directed histidine N(τ)-alkylation opens the door to new families of phosphopeptidomimetics for use in a range of chemical biology contexts.

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Synthesis and evaluation of novel macrocyclic antifungal peptides

Cited by 15 publications

References 40 publications

Effect of Disulfide Cyclization of Ultrashort Cationic Lipopeptides on Antimicrobial Activity and Cytotoxicity

Effect of Disulfide Cyclization of Ultrashort Cationic Lipopeptides on Antimicrobial Activity and Cytotoxicity

Synthesis of Cyclic Peptides and Peptidomimetics by Metathesis Reactions

Neighbor‐directed histidine N (τ)–alkylation: A route to imidazolium‐containing phosphopeptide macrocycles

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