A miniature mimic of host defense peptides with systemic antibacterial efficacy

@article{Sarig2010AMM,
  title={A miniature mimic of host defense peptides with systemic antibacterial efficacy},
  author={H. Sarig and L. Livne and Victoria Held-Kuznetsov and Fadia Zaknoon and A. Ivankin and D. Gidalevitz and A. Mor},
  journal={The FASEB Journal},
  year={2010},
  volume={24},
  pages={1904 - 1913}
}
Oligomers of acylated lysines (OAKs) are synthetic mimics of host defense peptides (HDPs) with promising antimicrobial properties. Here we challenged the OAK concept for its ability to generate both systemically efficient and economically viable lead compounds for fighting multidrug‐resistant bacteria. We describe the design and characterization of a miniature OAK composed of only 3 lysyls and 2 acyls (designated C12(ω7)K‐β12) that preferentially targets gram‐positive species by a… Expand
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References

SHOWING 1-10 OF 60 REFERENCES
Analogous oligo‐acyl‐lysines with distinct antibacterial mechanisms
TLDR
The data support the view that the analogous OAKs induced bacterial death by distinct mechanisms and suggest that relatively minor differences in the sequence of host defense peptides are responsible for selecting one mechanism over another, possibly in conjunction with differential binding affinities to the external and/or cytoplasmic membrane. Expand
Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides
TLDR
The in vitro activities of ampetoids are strikingly similar to those of AMPs themselves, suggesting a strong mechanistic analogy, and add to the growing evidence that nonnatural foldamers will emerge as an important class of therapeutics. Expand
Ultrashort antibacterial and antifungal lipopeptides
TLDR
The simple composition of these lipopeptides and their diverse specificities should make them economically available, innate immunity-mimicking antimicrobial and antifungal compounds for various applications. Expand
Antimicrobial peptide mimics for improved therapeutic properties.
TLDR
Most recent advances in the design strategies and the biophysical properties of the main classes of mimics to natural AMPs are reviewed, emphasizing the importance of structure-activity relationship studies in fine-tuning of their physicochemical attributes for improved antimicrobial properties. Expand
Antiplasmodial Activity of Lauryl-Lysine Oligomers
TLDR
An oligoacyllysine (OAK) tetramer designed to mimic the characteristics of dermaseptin was synthesized and assessed for its antimalarial activity, revealing that the ring and trophozoite stages of the parasite developmental cycle were equally sensitive to the compound. Expand
Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies
TLDR
The role of cationic host-defense peptides in modulating the innate immune response and boosting infection-resolving immunity while dampening potentially harmful pro-inflammatory (septic) responses gives these peptides the potential to become an entirely new therapeutic approach against bacterial infections. Expand
Amphiphilic poly(phenyleneethynylene)s can mimic antimicrobial peptide membrane disordering effect by membrane insertion.
TLDR
It is demonstrated that mPEs can mimic AMP's membrane disordering, and X-ray reflectivity measurements of the lipid/mPE system demonstrate that m PE molecules insert through the headgroup region and partially into the tail group region, thus accounting for the observed disordering of tail packing. Expand
Using Fluorous Amino Acids to Modulate the Biological Activity of an Antimicrobial Peptide
TLDR
Although promising as broad-spectrum antibiotics, AMPs are susceptible to proteolysis in vivo by endogenous or bacterial proteases, which can considerably diminish their effectiveness and attempt to overcome this problem by increasing the dose often leads to toxic side effects. Expand
Structure, membrane orientation, mechanism, and function of pexiganan--a highly potent antimicrobial peptide designed from magainin.
TLDR
Functional, biophysical, biochemical and structural studies on pexiganan are covered, showing that this peptide is unstructured in solution, forms an antiparallel dimer of amphipathic helices upon binding to the membrane, and disrupts membrane via toroidal-type pore formation. Expand
Structure-activity relationships of antibacterial acyl-lysine oligomers.
We describe structure-activity relationships that emerged from biophysical data obtained with a library of antimicrobial peptide mimetics composed of 103 oligoacyllysines (OAKs) designed to pin downExpand
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2
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4
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