- Effect of double replacement of L-Pro, D-Pro, D-Leu or Nleu in hydrophobic face of amphipathic α-helical model antimicrobial peptide on structure, cell selectivity and mechanism of action
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In order to investigate the effects of the double replacement of L-Pro, D-Pro, D-Leu or Nleu (the peptoid residue for Leu) in the hydrophobic face (positions 9 and 13) of amphipathic α-helical non-cell-selective antimicrobial peptide L8K9W1 on the structure, cell selectivity and mechanism of action, we synthesized a series of L8K9W1analogs with double replacement of L-Pro, D-Pro, D-Leu or Nleu in the hydrophobic face of L8K9W1. In this study, we have confirmed that the double replacement of L-Pro, D-Pro, or Nleu in the hydrophobic face of L8K9W1 let to a great increase in the selectivity toward bacterial cells and a complete destruction of α-helical structure. Interestingly, L8K9W1-L-Pro, L8K9W1-D-Pro and L8K9W1-Nleu preferentially interacted with negatively charged phospholipids, but unlike L8K9W1 and L8K9W1-D-Leu, they did not disrupt the integrity of lipid bilayers and depolarize the bacterial cytoplasmic membrane. These results suggested that the mode of action of L8K9W1-L-Pro, L8K9W1-D-Pro and L8K9W1-Nleu involves the intracellular target other than the bacterial membrane. In particular, L8K9W1-L-Pro, L8K9W1-D-Pro and L8K9W1-Nleu had powerful antimicrobial activity (MIC range, 1 to 4 μM) against methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Pseudomonas aeruginosa (MDRPA). Taken together, our results suggested that L8K9W1-L-Pro, L8K9W1-D-Pro and L8K9W1-Nleu with great cell selectivity may be promising candidates for novel therapeutic agents, complementing conventional antibiotic therapies to combat pathogenic microorganisms.
- Shin, Song Yub
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p. 3267 - 3274
(2015/04/22)
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- Development of cyclic peptomer inhibitors targeting the polo-box domain of polo-like kinase 1
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The polo-box domain (PBD) of polo-like kinase 1 (Plk1) is essentially required for the function of Plk1 in cell proliferation. The availability of the phosphopeptide-binding pocket on PBD provides a unique opportunity to develop novel protein-protein interaction inhibitors. Recent identification of a minimal 5-residue-long phosphopeptide, PLHSpT, as a Plk1 PBD-specific ligand has led to the development of several peptide-based inhibitors, but none of them is cyclic peptide. Through the combination of single-peptoid mimics and thio-ether bridged cyclization, we successfully demonstrated for the first time two cyclic peptomers, PL-116 and PL-120, dramatically improved the binding affinity without losing mono-specificity against Plk1 PBD in comparison with the linear parental peptide, PLHSpT. These cyclic peptomers could serve as promising templates for future drug designs to inhibit Plk1 PBD.
- Murugan, Ravichandran N.,Park, Jung-Eun,Lim, Dan,Ahn, Mija,Cheong, Chaejoon,Kwon, Taeho,Nam, Ky-Youb,Choi, Sun Ho,Kim, Bo Yeon,Yoon, Do-Young,Yaffe, Michael B.,Yu, Dae-Yeul,Lee, Kyung S.,Bang, Jeong Kyu
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p. 2623 - 2634
(2013/06/27)
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- HYDRAZIDE CONJUGATES AS IMAGING AGENTS
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The present disclosure is directed to diagnostic agents. More specifically, the disclosure is directed to compounds, diagnostic agents, compositions, and kits for detecting and/or imaging and/or monitoring a pathological disorder associated with coronary plaque, carotid plaque, aortic plaque, plaque of the arterial vessel, aneurism, vasculitis, and other diseases of the arterial wall. In addition, the disclosure is directed to methods of detecting and/or imaging and/or monitoring changes in the arterial wall, including expansive and constrictive remodeling, total vessel wall area, internal lumen size, and exterior artery perimeter.
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Page/Page column 43-44
(2010/11/25)
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- Solid-phase syntheses of peptoids using Fmoc-protected N-substituted glycines: The synthesis of (retro)peptoids of leu-enkephalin and substance P
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A particularly interesting class of oligomeric peptidomimetics is formed by the peptoids, which consist of N-substituted glycine residues. A solid- phase synthesis method for peptoids is presented in which these residues are introduced using their Fmoc derivatives. This 'monomer' method allowed the monitored synthesis of relatively large quantities of pure peptoids as well as the translation of, in principle, any peptide into the corresponding peptoid. The required Fmoc-substituted glycines were accessible by convenient synthesis, and a number of monomers including those containing side chains with functional groups have been synthesized. The use of Fmoc monomers also allowed implementation of a solid-phase synthesis protocol on a commercial peptide synthesizer. The method was exempli- fled by the solid-phase syntheses of the (retro)peptoids of Leu-enkephalin and substance P. Mass spectrometric studies of (retro)peptoids were essential for their characterization, and the presence of the B- and Y'- type ions allows sequence analysis. Substance P (retro)peptoids were biologically active. HPLC analysis showed an increased hydrophobicity, and pepsin treatment resulted in greatly reduced degradation compared with the corresponding peptide.
- Kruijtzer, John A.W.,Hofmeyer, Lovina J.F.,Heerma, Wigger,Versluis, Cornelis,Liskamp, Rob M.J.
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p. 1570 - 1580
(2007/10/03)
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