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1. |
Synthesis and alkylation of aza‐glycinyl dipeptide building blocks |
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Journal of Peptide Science,
Volume 19,
Issue 12,
2013,
Page 725-729
Yesica Garcia‐Ramos,
William D. Lubell,
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摘要:
Aza‐glycinyl dipeptides are useful building blocks for the synthesis of a diverse array of azapeptides. The construction of the aza‐glycine residue is however challenging, because of the potential for side reactions, such as those leading to formation of oxadiazalone, hydantoin and symmetric urea by‐products. EmployingN,N′‐disuccinimidyl carbonate to activate benzophenone hydrazone, we have developed a more efficient approach for the synthesis of aza‐glycinyl dipeptides. Alkylation of the semicarbazone of the resulting protected aza‐glycinyl dipeptides using tetraethylammonium hydroxide and propargyl bromide provided an efficient entry into the aza‐propargylglycinyl peptide building blocks, which have served previously in various reactions including Sonogashira cross‐couplings, dipolar cycloadditions and intramolecularexo‐digcycloadditions to furnish a variety of azapeptide building blocks. Copyright © 2013 European Peptide Society and
ISSN:1075-2617
DOI:10.1002/psc.2572
年代:2013
数据来源: WILEY
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2. |
A novel peptide specifically targeting ovarian cancer identified byin vivophage display |
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Journal of Peptide Science,
Volume 19,
Issue 12,
2013,
Page 730-736
Chuying Ma,
Guangfu Yin,
Danhong Yan,
Xueling He,
Li Zhang,
Yan Wei,
Zhongbing Huang,
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摘要:
Discovery of peptide ligands that can target human ovarian cancer and deliver chemotherapeutics offers new opportunity for cancer therapy. The advent of phage‐displayed peptide library facilitated the screening of such peptides.In vivoscreening that set in a microanatomic and functional context was applied in our study, and a novel peptide WSGPGVWGASVK targeting ovarian cancer was isolated. The phage clone PC3‐1 displaying peptide WSGPGVWGASVK can gain effective access to accumulate in the tumor sites after intravenous injection while reducing its accumulation in normal organs. Positive immunostaining of PC3‐1 was located in both sites of tumor cells and tumor blood vessels, which resulted in a diffuse binding pattern through the tumor.In vitrostudy results confirmed the capability of peptide WSGPGVWGASVK binding to and being internalized by both tumor cells and angiogenic endothelial cells. Flow cytometry analysis revealed that the peptide bound to SKOV3 cells with Kd value of 5.43 ± 0.4 μM. Taken together, it suggested that peptide WSGPGVWGASVK is a lead candidate for delivering therapeutics to penetrate into tumors. Copyright © 2013 European Peptide Society and John W
ISSN:1075-2617
DOI:10.1002/psc.2555
年代:2013
数据来源: WILEY
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3. |
Self‐assembly of pH and calcium dual‐responsive peptide‐amphiphilic hydrogel |
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Journal of Peptide Science,
Volume 19,
Issue 12,
2013,
Page 737-744
Xi‐Rui Zhou,
Rui Ge,
Shi‐Zhong Luo,
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摘要:
Peptide‐based hydrogels have gained much interest for biomedical applications as a result of their biocompatibility. Herein, we reported a synthetic pH‐sensitive and calcium‐responsive peptide‐amphiphilic hydrogel. The sequences of the peptide amphiphiles were derived from the repeat‐in‐toxin (RTX) motif. At a certain peptide‐amphiphile concentration, self‐assembly was accompanied by the formation of a rigid, viscoelastic hydrogel at low pH or the presence of calcium ions. Circular dichroism spectra showed that the peptide amphiphiles adopted beta‐sheet structure. Meanwhile, as revealed by transmission electron microscopy, the peptide‐amphiphile self‐assembly was accompanied by the formation of long interconnected nanofibrillar superstructure. Material properties of the resulting peptide‐amphiphile hydrogel were characterized using oscillatory sheer rheology, and the storage modulus (G′) was found to be one order of magnitude higher than the loss modulus (G″), indicating a moderately rigid viscoelastic material. Furthermore, with systematical residue substitution, it was found that the aspartic acid within the repeat‐in‐toxin sequence of peptide amphiphiles was responsible for the pH and calcium selectivity. The environmental responsiveness, secondary structure, morphology, and mechanical nature of the peptide‐amphiphile hydrogel make it a possible material candidate for biomedical and engineering application. Copyright © 2013 European Peptid
ISSN:1075-2617
DOI:10.1002/psc.2569
年代:2013
数据来源: WILEY
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4. |
An apolipoprotein E mimetic peptide with activities against multidrug‐resistant bacteria and immunomodulatory effects |
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Journal of Peptide Science,
Volume 19,
Issue 12,
2013,
Page 745-750
Chuan‐qing Wang,
Chang‐sheng Yang,
Yi Yang,
Fu Pan,
Lei‐yan He,
Ai‐min Wang,
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摘要:
Apolipoprotein E (apoE) mimetic peptides derived from the low‐density lipoprotein receptor‐binding region of apoE with both activities against multidrug‐resistant bacteria and immunomodulatory effects have not previously been reported. We identified an apoE mimetic peptide analogue of the receptor‐binding region of apoE (abbreviated as apoE23) with the sequence of LRKLRKRLVRLASHLRKLRKRLL, which exhibited high antibacterial effects. The minimal inhibitory concentration of apoE23 against multidrug‐resistantAcinetobacter baumanniiwas 6 µg/ml. The antimicrobial activity of apoE23 depended on its amphipathicα‐helical conformation. Moreover, apoE23 downregulated the expression of tumour necrosis factor‐α, interleukin‐6 and interleukin‐10 in lipopolysaccharide‐induced THP‐1 cells. ApoE23 exhibits potential in future clinical applications. Copyright © 2013 European Peptide Socie
ISSN:1075-2617
DOI:10.1002/psc.2570
年代:2013
数据来源: WILEY
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5. |
Site‐dependent biological activity of valinomycin analogs bearing derivatizable hydroxyl sites |
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Journal of Peptide Science,
Volume 19,
Issue 12,
2013,
Page 751-757
Cosimo Annese,
Daniela I. Abbrescia,
Lucia Catucci,
Lucia D'Accolti,
Nunzio Denora,
Immacolata Fanizza,
Caterina Fusco,
Gianluigi La Piana,
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摘要:
Valinomycin (VLM, 1) is a K+ionophore cyclodepsipeptide capable of depolarizing mitochondria and inducing apoptosis to several mammalian cell types, including a number of tumor cell lines. With the aim of creating VLM‐based ligand‐targeted anticancer drugs that may selectively convey VLM to pathological cells, we have previously introduced derivatizable hydroxyl handles into the VLM structure, allowing to access a three‐entity library of monohydroxyl VLMs (HyVLMs) bearing the OH group at the isopropyl side chain of ad‐Hyi,d‐Val, orl‐Val residue (analogs 2–4, respectively). Herein, the levels of bioactivity retained by the conjugable HyVLMs have been assessed on the basis of their ability to alter the functionality of isolated rat‐liver mitochondria. Experiments run with HyVLMs in the range 1–10 nM and in 20 or 125 mM KCl medium show that the hydroxyl group reduces the potency of HyVLMs relative to VLM to an extent that depends upon the molecular site involved in the hydroxylation. On the other hand, estimation of the stability constants of complexes (in methanol at 25 °C) of each analog with Na+, K+, and Cs+reveals that HyVLMs nicely retain the VLM binding features, except for a moderate increase in the stability of Na+complexes. These findings, along with pertinent structural considerations, suggest that the incorporation of OH into the VLM structure might actually have altered its K+transporting ability across mitochondrial membranes. Besides facing new aspects of VLM structure–activity relationship, these studies set the basis for the rational design of ligand‐HyVLMs conjugates through derivatization of hanging OH group. Copyright © 2013 European Peptide Socie
ISSN:1075-2617
DOI:10.1002/psc.2571
年代:2013
数据来源: WILEY
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6. |
The importance of being kinked: role of Pro residues in the selectivity of the helical antimicrobial peptide P5 |
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Journal of Peptide Science,
Volume 19,
Issue 12,
2013,
Page 758-769
Sara Bobone,
Gianfranco Bocchinfuso,
Yoonkyung Park,
Antonio Palleschi,
Kyung‐Soo Hahm,
Lorenzo Stella,
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摘要:
Antimicrobial peptides (AMPs) are promising compounds for developing new antibiotic drugs against drug‐resistant bacteria. Many of them kill bacteria by perturbing their membranes but exhibit no significant toxicity towards eukaryotic cells. The identification of the features responsible for this selectivity is essential for their pharmacological development. AMPs exhibit few conserved features, but a statistical analysis of an AMP sequence database indicated that manyα‐helical AMPs surprisingly have a helix‐breaking Pro residue in the middle of their sequence. To discriminate among the different possible hypotheses for the functional role of this feature, we designed an analogue of the antimicrobial peptide P5, in which the central Pro was deleted (analogue P5Del). Pro removal resulted in a dramatic increase of toxicity. This was explained by the observation that P5Del binds both charged and neutral membranes, whereas P5 has no appreciable affinity towards neutral bilayers. CD and simulative data provided a rationalization of this behavior. In solution P5, due to the presence of Pro, attains compact conformations, in which its apolar residues are partially shielded from the solvent, whereas P5Del is more helical. These structural differences reduce the hydrophobic driving force for association of P5 to neutral membranes, whereas its binding to anionic bilayers can still take place because of electrostatic attraction. After membrane binding, the Pro residue does not preclude the attainment of a membrane‐active amphiphilic helical conformation. These findings shed light on the role of Pro residues in the selectivity of AMPs and provide hints for the design of new, highly selective compounds. Copyright © 2013 European Peptide Society and John Wiley&
ISSN:1075-2617
DOI:10.1002/psc.2574
年代:2013
数据来源: WILEY
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7. |
Covalently attached fatty acyl chains alter the aggregation behavior of an amyloidogenic peptide derived from humanβ2‐microglobulin |
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Journal of Peptide Science,
Volume 19,
Issue 12,
2013,
Page 770-783
Anoop Rawat,
Ramakrishnan Nagaraj,
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摘要:
Aggregation of a polypeptide chain into highly ordered amyloid aggregates is a complex process. Various factors, both extrinsic and intrinsic to the polypeptide chain, have been shown to perturb this process, leading to a drastic change in the amyloidogenic behavior, which is reflected in the polymorphism of amyloid aggregates at various levels of self‐assembly. In this paper, we have investigated the ability of covalently linked long‐chain fatty acids in modulating the self‐assembly of an aromatic amino acid‐rich highly amyloidogenic sequence derived from the amino acid region 59–71 of humanβ2‐microglobulin by thioflavin T (ThT) fluorescence microscopy, circular dichroism, and fluorescence spectroscopy. Our results indicate that under identical conditions of dissolution and concentration, each peptide enhances the fluorescence of ThT. However, the aggregates are morphologically distinct. For the same peptide, the aggregate morphologies are dependent on peptide concentration. Further, an optimum concentration, which varies with solution ionic strength, is required for the formation of fibrillar aggregates. We show that covalent modification of this amyloidogenic sequence, with long‐chain fatty acids, affects the way the higher order amyloid structures assemble from the cross‐βunits, in fatty acyl chain‐dependent and position‐dependent manner. Our data indicate that noncovalent interactions leading to amyloid fibril formation can be modulated by the hydrophobicity of covalently attached long‐chain fatty acids resulting in self‐assembly of the peptide chain to form nonfibrillar aggregates. Copyright © 2013 European Peptide Societ
ISSN:1075-2617
DOI:10.1002/psc.2575
年代:2013
数据来源: WILEY
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8. |
Self‐assembling organo‐peptide bolaphiles with KLK tripeptide head groups display selective antibacterial activity |
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Journal of Peptide Science,
Volume 19,
Issue 12,
2013,
Page 784-791
Venthan B. Naidoo,
Marina Rautenbach,
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摘要:
In keeping with recent efforts to generate compounds for antibiotic and microbicide development, we focused on the creation of non‐natural organo‐peptide hybrids of antimicrobial peptide amides (KLK(L)nKLK‐NH2) derived from sapecin B and a self‐assembling oligoglycine organo‐peptide bolaphile containing anω‐amino fatty acid residue. The hybrid organo‐peptide bolaphiles with two cationic KLK tripeptide motifs linked with anω‐amino acid residue (penta‐, octa‐ or undecamethylene chain) maintained the self‐assembling properties of the root oligoglycine bolaphile. Electron microscopy clearly revealed complex supramolecular architectures for both sapecin B‐derived peptides and the hybrid analogues. FT‐IR spectroscopy indicated that the supramolecular structures were composed primarily ofβ‐sheets. CD revealed that the hybrid bolaphiles did not share the same secondary structures as the sapecin B peptides in solution. However, although secondary structures of antimicrobial peptides are central in the activity, the organo‐peptide bolaphiles also retained the potent antimicrobial activity of the leader sapecin B‐derived peptide against both Gram‐positive and Gram‐negative bacteria. In general, the hybrids were more selective than the sapecin B peptides, as they displayed little or no appreciable haemolytic activity. The results obtained herald a new approach for the design of purpose‐built hybrid organo‐peptide bolaphiles. Copyright © 2013 Europe
ISSN:1075-2617
DOI:10.1002/psc.2576
年代:2013
数据来源: WILEY
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9. |
Inhibitory effect of short cationic homopeptides against Gram‐positive bacteria |
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Journal of Peptide Science,
Volume 19,
Issue 12,
2013,
Page 792-800
Fanny Guzmán,
Sergio Marshall,
Claudia Ojeda,
Fernando Albericio,
Patricio Carvajal‐Rondanelli,
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摘要:
In the selection or design of antimicrobial peptides, the key role played by cationic amino acids and chain length on the inhibitory potency and specificity is not clear. A fundamental study was conducted using chemically synthesized homopeptides ofl‐Lys andl‐Arg ranging from 7 to 14 residues. Their effect on growth inhibition was evaluated over a wide range of Gram‐positive bacteria at different levels of concentration. Interestingly, at lower concentrations (10 μM), Lys homopeptides with odd number of residues, especially with 11 residues, showed a broader inhibitory activity than those with even number of residues. At higher peptide concentrations (>20 μM), the inhibitory activity of Lys homopeptides was directly related to the number of residues in the chain. In contrast, Arg homopeptides, at lower concentrations, did not exhibit a defined pattern of bacterial inhibition related to the number of residues; however, at higher concentrations (>20 μM), the inhibitory effects were more pronounced. Lys homopeptides at concentrations up to 300 μM showed a remarkably lower toxicity against CHSE‐214 cells. Arg homopeptides exhibited negligible cytotoxicity up to chain length of 11 residues at concentrations lower than 100 μM, but an abrupt increase in toxicity resulted when the peptide chain length reached 12 amino acid residues and higher concentrations. All synthesized homopeptides displayed characteristic polyproline II helix conformation in both buffer and liposomes, as shown by CD spectroscopy. This result suggests that short Lys homopeptides with an odd number of residues (9 and 11) have a broad spectrum of activity against Gram‐positive bacterial cells compared with Arg homopeptides, which in turn showed a considerably higher selectivity toward those cells. By investigating the differences between Lys and Arg homopeptides, this study contributes to the understanding of their mechanism of growth inhibition and selectivity. Thus, it provides further guidelines for a rational design of short antimicrobial peptides. Copyright © 2013 European Peptide Society
ISSN:1075-2617
DOI:10.1002/psc.2578
年代:2013
数据来源: WILEY
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