| 1. |
- Arsov, Zoran, et al.
(författare)
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Cholesterol prevents interaction of the cell-penetrating peptide transportan with model lipid membranes
- 2008
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Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 14:12, s. 1303-1308
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Tidskriftsartikel (refereegranskat)abstract
- Interaction of the cell-penetrating peptide (CPP) cysteine-transportan (Cys-TP) with model lipid membranes was examined by spin-label electron paramagnetic resonance (EPR). Membranes were labeled with lipophilic spin probes and the influence of Cys-TP on membrane structure Was studied. The influence of Cys-TP on membrane permeability was monitored by the reduction of a liposome-trapped water-soluble spin probe. Cys-TP caused lipid ordering in membranes prepared from pure dimyristoylphosphatidylcholine (DMPC) and in DMPC membranes with moderate cholesterol concentration. In addition, Cys-TP caused a large increase in permeation of DMPC membranes. In contrast, with high cholesterol content, at which model lipid membranes are in the so-called liquid-ordered phase, no effect. of Cys-TP was observed, either on Line membrane structure or on the membrane permeability. The interaction between Cys-TP and the lipid membrane therefore depends on the lipid phase. This could be of great. importance for understanding of the CPP-lipid interaction in laterally heterogeneous membranes, white it implies that the CPP-lipid interaction can be different at different points along the membrane.
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| 2. |
- Axén, Andreas, et al.
(författare)
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Cyclic insulin-regulated aminopeptidase (IRAP)/AT(4) receptor ligands
- 2006
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Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 12:11, s. 705-713
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Tidskriftsartikel (refereegranskat)abstract
- The angiotensin IV receptor (AT(4) receptor) is the insulin-regulated aminopeptidase enzyme (IRAP, EC 3.4.11.3). This membrane-spanning enzyme belongs to the M1 family of zinc-dependent metallo-peptidases. It has been proposed that AT4 receptor ligands exert their physiological effects by binding to the active site of IRAP and thereby inhibiting the catalytic activity of the enzyme. The biological activity of a large series of linear angiotensin IV analogs was previously disclosed. Herein, the synthesis and biological evaluation of a series of angiotensin IV analogs, encompassing macrocyclic ring systems of different sizes, are presented. It is demonstrated that disulfide cyclizations of angiotensin IV can deliver ligands with high IRAP/AT4 receptor affinity. One ligand, with an 11-membered ring system (4), inhibited human IRAP and aminopeptidase N (AP-N) activity with similar potency as angiotensin IV but was considerably more stable than angiotensin IV toward enzymatic degradation. The compound provides a promising starting point for further optimization toward more drug-like derivatives. The cyclic constrained analogs allowed us to propose a tentative bioactive conformation of angiotensin IV and it seems that the peptide adopts an inverse gamma-turn at the C-terminal.
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| 3. |
- Axén, Andreas, et al.
(författare)
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Small potent ligands to the insulin-regulated aminopeptidase (IRAP)/AT(4) receptor
- 2007
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Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 13:7, s. 434-444
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Tidskriftsartikel (refereegranskat)abstract
- Angiotensin IV analogs encompassing aromatic scaffolds replacing parts of the backbone of angiotensin IV have been synthesized and evaluated in biological assays. Several of the ligands displayed high affinities to the insulin-regulated aminopeptidase (IRAP)/AT4 receptor. Displacement of the C-terminal of angiotensin IV with an o-substituted aryl acetic acid derivative delivered the ligand 4, which exhibited the highest binding affinity (Ki = 1.9 nM). The high affinity of this ligand provides support to the hypothesis that angiotensin IV adopts a -turn in the C-terminal of its bioactive conformation.Ligand (4) inhibits both human IRAP and aminopeptidase N-activity and induces proliferation of adult neural stem cells at low concentrations. Furthermore, ligand 4 is degraded considerably more slowly in membrane preparations than angiotensin IV. Hence, it might constitute a suitable research tool for biological studies of the (IRAP)/AT4 receptor.
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| 4. |
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| 5. |
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| 6. |
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| 7. |
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| 8. |
- Ericsson, Daniel J., et al.
(författare)
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Identification of small peptides mimicking the R2 C-terminus of Mycobacterium tuberculosis ribonucleotide reductase
- 2010
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Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 16:3, s. 159-164
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Tidskriftsartikel (refereegranskat)abstract
- Ribonucleotide reductase (RNR) is a viable target for new drugs against the causative agent of tuberculosis, Mycobacterium tuberculosis. Previous work has shown that an N-acetylated heptapeptide based on the C-terminal sequence of the smaller RNR subunit can disrupt the formation of the holoenzyme sufficiently to inhibit its function. Here the synthesis and binding affinity, evaluated by competitive fluorescence polarization, of several truncated and N-protected peptides are described. The protected single-amino acid Fmoc-Trp shows binding affinity comparable to the N-acetylated heptapeptide, making it an attractive candidate for further development of non-peptidic RNR inhibitors.
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| 9. |
- Forde, Eanna, et al.
(författare)
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Action of antimicrobial peptides and their prodrugs on model and biological membranes
- 2018
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Ingår i: Journal of Peptide Science. - : WILEY. - 1075-2617 .- 1099-1387. ; 24:7
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Tidskriftsartikel (refereegranskat)abstract
- Antimicrobial peptides (AMPs) are promising broad-spectrum antibiotic candidates in the wake of multi-drug resistant pathogens. Their clinical use still requires a solution based on lead optimisation and/ or formulation to overcome certain limitations, such as unwanted cytotoxicity. A prodrug approach could overcome this safety barrier and can be achieved through reversible reduction or neutralisation of the AMPs' net cationic charge. By prodrug activation through pathogen associated enzymes, this approach could increase the therapeutic index of membrane active peptides. P18, a cecropin/ magainin hybrid, and WMR, a myxinidin analogue from hagfish, were used as templates for the design strategy. The membrane permeabilizing activities of these AMPs and their prodrugs are reported here for liposomes of either Escherichia coli polar lipid extract or a human model lipid system of phosphatidylcholine and cholesterol. These results are compared with their antibacterial and haemolytic activities. Overall, correlation between liposome permeabilization and the corresponding bioactivity is observed and indicate that the broad-spectrum antibacterial effect exerted by these peptides is associated with membrane disruption. Furthermore, the prodrug modification had a general negative influence on membrane disruption and bioactivity, notably as much on bacterial as on human membranes. This prodrug strategy is particularly successful when complete neutralisation of the AMP's net charge occurs. Thus, on-target selectivity between bacterial and human membranes can be improved, which may be used to prevent the unnecessary exposure of host cells and commensal bacteria to active AMPs.
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| 10. |
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| 11. |
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| 12. |
- Gunasekera, Sunithi, et al.
(författare)
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Fmoc-SPPS based synthesis of bioactive cyclic peptides via N-acylurea intermediates
- 2012
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Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 18:suppl 1, s. S182-S182
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The plant cyclotides form the largest family of cyclic peptides(1). They contain a signature motif referred to as the cyclic cystine knot, which is derived from the cyclic backbone and three inter-knotted disulfide bonds. Intriguingly, cyclotides can be boiled, treated with chemicals or enzymes without disrupting their overall fold. Thus, they are sometimes labeled as ultra-stable proteins. In addition, cyclotides are tolerant to mutations, and as a scaffold they can successfully accommodate foreign bioactive epitopes of variable sequences(2). Cyclotides share many of these properties with another disulfide containing cyclic plant peptide, the sunflower trypsin inhibitor 1 (SFTI-1)(3). Emerging evidence indicates that cyclotides and SFTI-1 are valuable not only as peptide stabilizing scaffolds; in combination with their cell penetrating properties, these disulfide rich cyclic peptides have significance as intracellular drug carriers. Although both peptides are genetically encoded, studies to ascertain the exact mechanisms of their biosynthesis are currently on going. Thus, the synthesis of cyclotides and SFTI-1 are currently restricted to chemical means. We have recently adapted a Fmoc-SPPS method for cyclic peptide synthesis, via N-acylurea intermediates with the assistance of microwave irradiation.This method is a safe and convenient alternative to Boc-SPPS and has the ability to be automated conveniently. Using this method, parent scaffolds as well as several cyclotide and SFTI-1 analogues with potential antimicrobial and matrix metalloprotease activities were synthesized. With the rising interest in the cyclization concept as a tool to impart stability on unstable peptides, the cyclic peptide synthesis method adapted herein is anticipated to have numerous applications.1. Burman, R.; Gunasekera, S.; Stromstedt, A.; Rosengren, J.; Goransson, U. J. Biol. Chem. 2012 (in press)2. Gunasekera, S.; Foley, F. M.; Clark, R. J.; Sando, L.; Fabri, L. J.; Craik, D. J.; Daly, N. L. J. Med. Chem. 2008, 51, 7697.3. Chan, L. Y.; Gunasekera, S.; Henriques, S. T.; Worth, N. F.; Le, S. J.; Clark, R. J.; Campbell, J. H.; Craik, D. J.; Daly, N. L. Blood 2011, 118, 6709.
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| 13. |
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| 14. |
- Ismail, Naadhira O, et al.
(författare)
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Antimicrobial function of short amidated peptide fragments from the tick-derived OsDef2 defensin.
- 2019
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Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 25:12
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Tidskriftsartikel (refereegranskat)abstract
- Previously Os, a 22 amino acid sequence of a defensin from the soft tick Ornithodoros savignyi, was found to kill Gram-positive and Gram-negative bacteria at low micromolar concentrations. In this study, we evaluated synthetic peptide analogues of Os for antibacterial activity with an aim to identify minimalized active peptide sequences and in so doing obtain a better understanding of the structural requirements for activity. Out of eight partially overlapping sequences of 10 to 12 residues, only Os(3-12) and Os(11-22) exhibit activity when screened against Gram-positive and Gram-negative bacteria. Carboxyamidation of both peptides increased membrane-mediated activity, although carboxyamidation of Os(11-22) negatively impacted on activity against Staphylococcus aureus. The amidated peptides, Os(3-12)NH2 and Os(11-22)NH2 , have minimum bactericidal concentrations of 3.3 μM against Escherichia coli. Killing was reached within 10 minutes for Os(3-12)NH2 and only during the second hour for Os(11-22)NH2 . In an E. coli membrane liposome system, both Os and Os(3-12)NH2 were identified as membrane disrupting while Os(11-22)NH2 was less active, indicating that in addition to membrane permeabilization, other targets may be involved in bacterial killing. In contrast to Os, the membrane disruptive effect of Os(3-12)NH2 did not diminish in the presence of salt. Neither Os nor its amidated derivatives caused human erythrocyte haemolysis. The contrasting killing kinetics and effects of amidation together with structural and liposome leakage data suggest that the 3-12 fragment relies on a membrane disruptive mechanism while the 11-22 fragment involves additional target mechanisms. The salt-resistant potency of Os(3-12)NH2 identifies it as a promising candidate for further development.
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| 15. |
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| 16. |
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| 17. |
- Järver, Peter, et al.
(författare)
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Chemical synthesis and evaluation of a backbone-cyclized minimized 2-helix Z-domain
- 2011
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Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 17:6, s. 463-469
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Tidskriftsartikel (refereegranskat)abstract
- The Z-molecule is a small, engineered IgG-binding affinity protein derived from the immunoglobulin-binding domain B of Staphylococcus aureus protein A. The Z-domain consists of 58 amino acids forming a well-defined antiparallel three-helix structure. Two of the three helices are involved in ligand binding, whereas the third helix provides structural support to the three-helix bundle. The small size and the stable three-helix structure are two attractive properties comprised in the Z-domain, but a further reduction in size of the protein is valuable for several reasons. Reduction in size facilitates synthetic production of any protein-based molecule, which is beneficial from an economical viewpoint. In addition, a smaller protein is easier to manipulate through chemical modifications. By omitting the third stabilizing helix from the Z-domain and joining the N- and C-termini by a native peptide bond, the affinity protein obtains the advantageous properties of a smaller scaffold and in addition becomes resistant to exoproteases. We here demonstrate the synthesis and evaluation of a novel cyclic two-helix Z-domain. The molecule has retained affinity for its target protein, is resistant to heat treatment, and lacks both N- and C-termini. Copyright (C) 2011 European Peptide Society and John Wiley & Sons, Ltd.
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| 18. |
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| 19. |
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| 20. |
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| 21. |
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| 22. |
- Khemtémourian, Lucie, et al.
(författare)
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Synthesis and secondary structure in membranes of the Bcl-2 anti-apoptotic domain BH4
- 2006
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Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 12, s. 58-64
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Tidskriftsartikel (refereegranskat)abstract
- Solid phase synthesis of BH4, the 26 amino-acid domain (6RTGYDNREIVMKYIHYKLSQRGYEWD31) of the anti-apoptotic Bcl-2 protein has been accomplished using Fmoc chemistry. The use of peculiar cleavage conditions provided high yields after purification such that tens to hundreds of mg could be obtained. A 15N-labelled version of the peptide could also be synthesized for NMR studies in membranes. The peptide purity was not lower than 98% as controlled by UV and MALDI-TOF mass spectrometry. The secondary structure was determined in water, trifluoroethanol (TFE) and in lipid membrane using UV circular dichroism. The peptide shows dominant -sheeted structures in water that convert progressively into -helical features upon addition of TFE or membrane. The amphipathic character of the helix suggests that the peptide might have a structure akin to those of antimicrobial peptides upon interaction with membranes. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd.
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| 23. |
- Labriere, C., et al.
(författare)
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Development and evaluation of cationic amphiphilic antimicrobial 2,5-diketopiperazines
- 2018
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Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 24:7
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Tidskriftsartikel (refereegranskat)abstract
- Both pathogenic bacteria and fungi are developing resistance to common antimicrobial treatment at an alarming rate. To counteract this development, it is of essence to develop new classes of antimicrobial agents. One such class is antimicrobial peptides, most of which are derived from the innate immune system. In this study, a series of novel 2,5-diketopiperazines were designed, synthesized, and evaluated for their antimicrobial abilities. The compounds were designed to probe the pharmacophore dictated for short linear mimics of antimicrobial cationic peptides, and as such, the compounds contain a range of cationic and hydrophobic functionalities. Several of the prepared compounds displayed high antimicrobial activities toward bacteria and also against human pathogenic fungi. Of particular interest was the high activity toward fungal strains with an inherent increased resistance toward conventional antifungal agents. The most effective compounds displayed inhibition of Candida glabrata and Candida krusei growth at concentrations between 4 and 8 mu g/mL, which is comparable to commercial antifungal agents in use. Structure activity relationship studies revealed a similar dependence on cationic charge and the volume of the hydrophobic bulk as for linear cationic antimicrobial peptides. Finally, the hemolytic activity of selected compounds was evaluated, which revealed a potential to produce active compounds with attenuation of unwanted hemolysis. The findings highlight the potential of cyclic cationic amphiphilic peptidomimetics as a class of promising compounds for the treatment of infections caused by microorganisms with an increased resistance to conventional antimicrobial agents.
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| 24. |
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| 25. |
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| 26. |
- Malik, Leila, et al.
(författare)
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Self-assembly of designed coiled coil peptides studied by small-angle X-ray scattering and analytical ultracentrifugation
- 2013
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Ingår i: Journal of Peptide Science. - : Wiley. - 1099-1387 .- 1075-2617. ; 19:5, s. 283-292
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Tidskriftsartikel (refereegranskat)abstract
- alpha-Helical coiled coil structures, which are noncovalently associated heptad repeat peptide sequences, are ubiquitous in nature. Similar amphipathic repeat sequences have also been found in helix-containing proteins and have played a central role in de novo design of proteins. In addition, they are promising tools for the construction of nanomaterials. Small-angle X-ray scattering (SAXS) has emerged as a new biophysical technique for elucidation of protein topology. Here, we describe a systematic study of the self-assembly of a small ensemble of coiled coil sequences using SAXS and analytical ultracentrifugation (AUC), which was correlated with molecular dynamics simulations. Our results show that even minor sequence changes have an effect on the folding topology and the self-assembly and that these differences can be observed by a combination of AUC, SAXS, and circular dichroism spectroscopy. A small difference in these methods was observed, as SAXS for one peptide and revealed the presence of a population of longer aggregates, which was not observed by AUC. Copyright (c) 2013 European Peptide Society and John Wiley & Sons, Ltd.
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| 27. |
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| 28. |
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| 29. |
- Mandrika, Ilona, et al.
(författare)
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Improving the affinity of antigens for mutated antibodies by use of statistical molecular design
- 2008
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Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 14:7, s. 786-96
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Tidskriftsartikel (refereegranskat)abstract
- We demonstrate the use of statistical molecular design (SMD) in the selection of peptide libraries aimed to systematically investigate antigen-antibody binding spaces. Earlier, we derived two novel antibodies by mutating the complementarity-determining region of the anti-p24 (HIV-1) single chain Fv antibody, CB4-1 that had lost their affinity for a p24 epitope-homologous peptide by 8- and 60-fold. The present study was devoted to explore how peptide libraries can be designed under experimental design criteria for effective screening of peptide antigens. Several small peptide-antigen libraries were selected using SMD principles and their activities were evaluated by their binding to SPOT-synthesized peptide membranes and by fluorescence polarization (FP). The approach was able to reveal the most critical residues required for antigen binding, and finally to increase the binding activity by proper modifications of amino acids in the peptide antigen. A model of the active peptide binding pocket formed by the mutated scFv and the antigen was compatible with the information gained from the experimental data. Our results suggest that SMD approaches can be used to explore peptide antigen features essential for their interactions with antibodies.
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| 30. |
- Mbuayama, Kabuzi R., et al.
(författare)
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Antifungal activity and mode of action of synthetic peptides derived from the tick OsDef2 defensin
- 2022
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Ingår i: Journal of Peptide Science. - : John Wiley & Sons. - 1075-2617 .- 1099-1387. ; 28:5
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Tidskriftsartikel (refereegranskat)abstract
- Candida albicans is the principal opportunistic fungal pathogen in nosocomial settings and resistance to antifungal drugs is on the rise. Antimicrobial peptides from natural sources are promising novel therapeutics against C. albicans. OsDef2 defensin was previously found to be active against only Gram-positive bacteria, whereas derived fragments Os and its cysteine-free analogue, Os-C, are active against Gram-positive and Gram-negative bacteria at low micromolar concentrations. In this study, OsDef2-derived analogues and fragments were screened for anticandidal activity with the aim to identify peptides with antifungal activity and in so doing obtain a better understanding of the structural requirements for activity and modes of action. Os, Os-C and Os(11-22)NH2 , a Os-truncated carboxy-terminal-amidated fragment, had the most significant antifungal activities, with minimum fungicidal concentrations (MFCs) in the micromolar range (6-28 μM). C. albicans killing was rapid and occurred within 30-60 min. Further investigations showed all three peptides interacted with cell wall derived polysaccharides while both Os and Os(11-22)NH2 permeabilized fungal liposomes. Confocal laser scanning microscopy confirmed that Os-C and Os(11-22)NH2 could enter the cytosol of live cells and subsequent findings suggest that the uptake of Os and Os-C, in contrast to Os(11-22)NH2 , is energy dependent. Although Os, Os-C and Os(11-22)NH2 induced the production of reactive oxygen species (ROS), co-incubation with ascorbic acid revealed that only ROS generated by Os-C and to a lesser extent Os(11-22)NH2 resulted in cell death. Overall, Os, Os-C and Os(11-22)NH2 are promising candidacidal agents.
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| 31. |
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| 32. |
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| 33. |
- Norgren, Anna S., et al.
(författare)
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Glycosylated Foldamers : Synthesis of Carbohydrate-modified β3hSer and Incorporation into β-Peptides
- 2007
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Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 13:11, s. 717-727
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Tidskriftsartikel (refereegranskat)abstract
- Fmoc-protected β3hserine (β3hSer) was prepared and O-linked to suitably protected N-acetylgalactosamine (GalNAc) and N-acetylglucosamine (GlcNAc) derivatives. Glycosylation of β3hSer was made by two independent routes: either by direct glycosyl linkage to the β3hSer, or linkage to natural L-Ser and then utilizing the carbohydrate moiety as a protecting group in an Arndt–Eistert homologation. Both procedures gave the novel glycosylated β3-amino acids Fmoc-β3hSer(α-D-GalNAc(Ac)3)-OH (1a), its β-anomer (1b), and Fmoc-β3hSer(β-D-GlcNAc(Ac)3)-OH (2), which were utilized in the solid-phase peptide synthesis of four glycosylated dipeptides (3a–d) and two heptapeptides (4a–b). The preparation of β-amino acids bearing common post-translational modifiers represents an important step towards functionalized foldamers with broad applications in biomedical research.
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| 34. |
- Nurbo, Johanna, et al.
(författare)
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Design, synthesis and evaluation of peptide inhibitors of Mycobacterium tuberculosis ribonucleotide reductase
- 2007
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Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 13:12, s. 822-832
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Tidskriftsartikel (refereegranskat)abstract
- Mycobacterium tuberculosis ribonucleotide reductase (RNR) is a potential target for new antitubercular drugs. Herein we describe the synthesis and evaluation of peptide inhibitors of RNR derived from the C-terminus of the small subunit of M. tuberculosis RNR. An N-terminal truncation, an alanine scan and a novel statistical molecular design (SMD) approach based on the heptapeptide Ac-Glu-Asp-Asp-Asp-Trp-Asp-Phe-OH were applied in this study. The alanine scan showed that TrP5 and Phe7 were important for inhibitory potency. A quantitative structure relationship (QSAR) model was developed based on the synthesized peptides which showed that a negative charge in positions 2, 3, and 6 is beneficial for inhibitory potency. Finally, in position 5 the model coefficients indicate that there is room for a larger side chain., as compared to Trp5.
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| 35. |
- Papareddy, Praveen, et al.
(författare)
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Antimicrobial activity of peptides derived from human ß-amyloid precursor protein.
- 2012
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Ingår i: Journal of Peptide Science. - : Wiley. - 1099-1387 .- 1075-2617. ; 18:3, s. 183-191
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Tidskriftsartikel (refereegranskat)abstract
- Antimicrobial peptides are important effector molecules of the innate immune system. Here, we describe that peptides derived from the heparin-binding disulfide-constrained loop region of human ß-amyloid precursor protein are antimicrobial. The peptides investigated were linear and cyclic forms of NWCKRGRKQCKTHPH (NWC15) as well as the cyclic form comprising the C-terminal hydrophobic amino acid extension FVIPY (NWCKRGRKQCKTHPHFVIPY; NWC20c). Compared with the benchmark antimicrobial peptide LL-37, these peptides efficiently killed the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, the Gram-positive Staphylococcus aureus and Bacillus subtilis, and the fungi Candida albicans and Candida parapsilosis. Correspondingly, fluorescence and electron microscopy demonstrated that the peptides caused defects in bacterial membranes. Analogously, the peptides permeabilised negatively charged liposomes. Despite their bactericidal effect, the peptides displayed very limited hemolytic activities within the concentration range investigated and exerted very small membrane permeabilising effects on human epithelial cells. The efficiency of the peptides with respect to bacterial killing and liposome membrane leakage was in the order NWC20c > NWC15c > NWC15l, which also correlated to the adsorption density for these peptides at the model lipid membrane. Thus, whereas the cationic sequence is a minimum determinant for antimicrobial action, a constrained loop-structure as well as a hydrophobic extension further contributes to membrane permeabilising activity of this region of amyloid precursor protein. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.
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| 36. |
- Park, SungKyu, et al.
(författare)
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Microwave-assisted total synthesis of macrocyclic cystine knot miniproteins
- 2010
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Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 16:S1, s. 79-79
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Microwave-assisted total synthesis of macrocyclic cystine knot miniproteins SK Park, S Gunasekera, T Aboye, U Göransson Division of pharmacognosy, Uppsala university, UPPSALA, Sweden Cyclotides are mini-proteins of approximately 30 amino acids residues that have a unique structure consisting of a head-to-tail cyclic backbone with a knotted arrangement of three disulfide bonds [1]. This unique structure provides exceptional stability to chemical, enzymatic and thermal treatments [2,3]. Cyclotides display various bioactivities, such as anti-HIV, uterotonic, cytotoxic, and insecticidal activity [4]. Due to the unique structural stability, cyclotides have been implicated as ideal drug scaffolds and for development into agricultural and biotechnological agents [2]. In the current work, we represent the first method for total synthesis of cyclotides based on Fmoc-SPPS assisted by microwave. This protocol adopts a strategy that combines the optimized microwave assisted chemical reactions for Fmoc-SPPS of peptide backbone synthesis, thioesterification of the C-terminal carboxylic acid of the peptide and a one pot reaction that promotes cyclisation through native chemical ligation and oxidative folding. The application of this protocol was exemplified for the synthesis of two prototypic cyclotides; kalata B1 and MCOTI-II
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| 37. |
- Paulsen, Marianne H., et al.
(författare)
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An amphipathic cyclic tetrapeptide scaffold containing halogenated β2,2-amino acids with activity against multiresistant bacteria
- 2018
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Ingår i: Journal of Peptide Science. - : John Wiley & Sons. - 1075-2617 .- 1099-1387. ; 24:10
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Tidskriftsartikel (refereegranskat)abstract
- The present study describes the synthesis and biological studies of a small series of head-to-tail cyclic tetrapeptides of the general structure c(Lys‐β2,2‐Xaa‐Lys) containing one lipophilic β2,2-amino acid and Lys, Gly, Ala, or Phe as the Xaa residue in the sequence. The peptides were investigated for antimicrobial activity against gram-positive and gram-negative reference strains and 30 multiresistant clinical isolates including strains with extended spectrum β-lactamase-carbapenemase (ESBL-CARBA) production. Toxicity was determined against human red blood cells. The most potent peptides showed high activity against the gram-positive clinical isolates with minimum inhibitory concentrations of 4-8μg/mL and low haemolytic activity. The combination of high antimicrobial activity and low toxicity shows that these cyclic tetrapeptides containing lipophilic β2,2-amino acids form a valuable scaffold for designing novel antimicrobial agents.
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| 38. |
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| 39. |
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| 40. |
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| 41. |
- Pudelko, Maciej, et al.
(författare)
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Application of gel-phase 19F NMR spectroscopy for optimization of solid-phase synthesis of a hydrophobic peptide from the signal sequence of the mucin MUC1
- 2007
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Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 13:5, s. 354-361
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Tidskriftsartikel (refereegranskat)abstract
- This paper describes the manual Fmoc/t-Bu solid-phase synthesis of a difficult nine-residue hydrophobic peptide LLLLTVLTV from one of the signal sequences that flank the tandem repeat of the mucin MUC1. Gel-phase 19F NMR spectroscopy was used as a straightforward method for optimization of the solid-phase synthesis. Different approaches were applied for comparative studies. The strategy based on modified solid-phase conditions using DIC/HOAt for coupling, DBU for Fmoc deprotection, and the incorporation of the pseudo proline dipeptide Fmoc-Leu-Thr(Me, Me pro)-OH as a backbone-protecting group was found to be superior according to gel-phase 19F NMR spectroscopy. Implementation of the optimized Fmoc protocol enabled an effective synthesis of signal peptide LLLLTVLTV.
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| 42. |
- Pudelko, Maciej, et al.
(författare)
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Synthesis and application of N-[1-(4-(4-fluorophenyl)-2,6-dioxocyclohexylidene)ethyl] (Fde)-protected amino acids for optimization of solid-phase peptide synthesis using gel-phase (19)F NMR spectroscopy.
- 2009
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Ingår i: Journal of Peptide Science. - : European Peptide Society and John Wiley & Sons, Ltd.. - 1075-2617 .- 1099-1387. ; 15:4, s. 264-71
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Tidskriftsartikel (refereegranskat)abstract
- N-[1-(4-(4-fluorophenyl)-2,6-dioxocyclohexylidene)ethyl] (Fde) protected amino acids have been prepared and applied in solid-phase peptide synthesis monitored by gel-phase (19)F NMR spectroscopy. The Fde protective group could be cleaved with 2% hydrazine or 5% hydroxylamine solution in DMF as determined with gel-phase (19)F NMR spectroscopy. The dipeptide Ac-L-Val-L-Val-NH(2) 12 was constructed using Fde-L-Val-OH and no noticeable racemization took place during the amino acid coupling with N,N'-diisopropylcarbodiimide and 1-hydroxy-7-azabenzotriazole or Fde deblocking. To extend the scope of Fde protection, the hydrophobic nonapeptide LLLLTVLTV from the signal sequence of mucin MUC1 was successfully prepared using Fde-L-Leu-OH at diagnostic positions. Copyright (c) 2009 European Peptide Society and John Wiley & Sons, Ltd.
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| 43. |
- Rydberg, Johan, et al.
(författare)
-
Intrinsically unstructured proteins by designelectrostatic interactions can control binding, folding, and function of a helix-loop-helix heterodimer
- 2013
-
Ingår i: Journal of Peptide Science. - : Wiley-Blackwell. - 1075-2617 .- 1099-1387. ; 19:8, s. 461-469
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Tidskriftsartikel (refereegranskat)abstract
- Intrinsically disordered proteins that exist as unordered monomeric structures in aqueous solution at pH7 but fold into four-helix bundles upon binding to recognized polypeptide targets have been designed. NMR and CD spectra of the monomeric polypeptides show the hallmarks of unordered structures, whereas in the bound state they are highly helical. Analytical ultracentrifugation data shows that the polypeptides bind to their targets to form exclusively heterodimers at neutral pH. To demonstrate the relationship between binding, folding, and function, a catalytic site for ester hydrolysis was introduced into an unordered and largely inactive monomer, but that was structured and catalytically active in the presence of a specific polypeptide target. Electrostatic interactions between surface-exposed residues inhibited the binding and folding of the monomers at pH7. Charge-charge repulsion between ionizable amino acids was thus found to be sufficient to disrupt binding between polypeptide chains despite their inherent propensities for structure formation and may be involved in the folding and function of inherently disordered proteins in biology.
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| 44. |
- Sani, Marc-Antoine, et al.
(författare)
-
Pro-apoptotic bax-α1 synthesis and evidence for β-sheet to α-helix conformational change as triggered by negatively charged lipid mβembranes
- 2007
-
Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 13:2, s. 100-106
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Tidskriftsartikel (refereegranskat)abstract
- Solid phase synthesis of Bax-α1, the 25 amino acids domain (14TSSEQIMKTGALLLQGFIQDRAGRM38) of the pro-apoptotic Bax protein has been accomplished using Fmoc chemistry. A new fast and harmless protocol is described for complete TFA removal from the purified peptide powder leading to a final purity greater than 98% as controlled by 19F-NMR, UV and MALDI-TOF mass spectrometry. Secondary structure was determined in various solution and membrane media using UV Circular Dichroism. In water solution, Bax-α1 is present as a mixture of β-sheet and unstructured (random coil) conformations. A marked change from β-sheet to α-helix secondary structures is observed upon interaction with negatively charged phospholipids vesicles whereas neutral lipid membranes have no significant effect on the aqueous peptide conformation. Results are discussed in terms of Bax binding to mitochondrial membranes.
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| 45. |
- Sayer, James R., et al.
(författare)
-
Design, synthesis, and evaluation of peptide-imidazo[1,2-a]pyrazine bioconjugates as potential bivalent inhibitors of the VirB11 ATPase HP0525
- 2021
-
Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 27:10
-
Tidskriftsartikel (refereegranskat)abstract
- Helicobacter pylori (H. pylori) infections have been implicated in the development of gastric ulcers and various cancers: however, the success of current therapies is compromised by rising antibiotic resistance. The virulence and pathogenicity of H. pylori is mediated by the type IV secretion system (T4SS), a multiprotein macromolecular nanomachine that transfers toxic bacterial factors and plasmid DNA between bacterial cells, thus contributing to the spread of antibiotic resistance. A key component of the T4SS is the VirB11 ATPase HP0525, which is a hexameric protein assembly. We have previously reported the design and synthesis of a series of novel 8-amino imidazo[1,2-a]pyrazine derivatives as inhibitors of HP0525. In order to improve their selectivity, and potentially develop these compounds as tools for probing the assembly of the HP0525 hexamer, we have explored the design and synthesis of potential bivalent inhibitors. We used the structural details of the subunit-subunit interactions within the HP0525 hexamer to design peptide recognition moieties of the subunit interface. Different methods (cross metathesis, click chemistry, and cysteine-malemide) for bioconjugation to selected 8-amino imidazo[1,2-a]pyrazines were explored, as well as peptides spanning larger or smaller regions of the interface. The IC50 values of the resulting linker-8-amino imidazo[1,2-a]pyrazine derivatives, and the bivalent inhibitors, were related to docking studies with the HP0525 crystal structure and to molecular dynamics simulations of the peptide recognition moieties.
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| 46. |
- Sladewska, A. S., et al.
(författare)
-
Characteristics of hCC-mAb complex
- 2010
-
Ingår i: Journal of Peptide Science. - : Wiley. - 1099-1387 .- 1075-2617. ; 16, s. 111-112
-
Konferensbidrag (refereegranskat)
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| 47. |
- Ślósarczyk, Adam T., 1983-, et al.
(författare)
-
Efficient formation of heterodimers from peptides and proteins using unsymmetrical polyfluorophenyl esters of dicarboxylic acids
- 2012
-
Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 18:4, s. 261-269
-
Tidskriftsartikel (refereegranskat)abstract
- An efficient method for the heteroconjugation of biomolecules carrying free amino groups was reported previously, where mixed polyfluorophenyl diesters of dicarboxylic acids with varied aliphatic chain length were shown to be efficient reagents for the conjugation of a variety of model biomolecules. The concept was based on the differential reactivity of the esters towards amines. The concept has now been further optimized, and a 2,6-difluorophenyl-pentafluorophenyl diester combination has been demonstrated to be the most efficient, both with respect to selectivity and to reaction rate. A pentafluorophenyl ester reacts faster with an amino group and requires a weaker base than a 2,6-difluorophenyl ester that requires a stronger base and longer reaction time. With the use of this combination of esters, we obtained considerably shortened reaction times compared with those reported previously, yet still retaining the desired selectivity in heteroconjugation. The increased reactivity of the bifunctional reagent allowed the construction of sophisticated peptide heteroconjugates from peptides, carbohydrates and proteins, showing a wide scope of applicability in the field of assembling functional bioconjugates.
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| 48. |
- Sun, Xiaojiao, et al.
(författare)
-
A synthetic polypeptide conjugate from a 42-residue polypeptide and salicylhydroxamic acid binds human myeloperoxidase with high affinity
- 2012
-
Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 18:12, s. 731-739
-
Tidskriftsartikel (refereegranskat)abstract
- Myeloperoxidase (MPO) is a 150 kD tetrameric heme protein consisting of two heavy chains and two light chains, which ispresent in neutrophils, white blood cells, at concentrations between 2% and 5% and plays an important role in the innateimmune system. The MPO concentration in serum or plasma has been shown to be linked to the risk for cardiovasculardiseases, and MPO is considered to be a high potential diagnostic biomarker. To develop a molecule that binds MPO,salicylhydroxamic acid (SHA), a substrate analog inhibitor of MPO with a KD=2uM, was conjugated to a designed set of42-residue polypeptide scaffolds via 9- and 11-carbon atom aliphatic spacers to form 20 different protein binder candidates,and their interactions with MPO were evaluated by surface plasmon resonance analysis. The polypeptide conjugate4C37L34C11SHA was found to bind to MPO with an affinity that could be estimated to have a dissociation constant of around400 pM, nearly four orders of magnitude higher than that of SHA. Inhibition of binding to MPO by free SHA was observed incompetition experiments demonstrating that the binding of the polypeptide conjugate is dominated by the interactions ofSHA with the heme cavity. Although still in the future, the discovery of these new synthetic binders for MPO suggests aroute to clinical diagnostic tests in vivo or in vitro, independent of antibodies.
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| 49. |
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| 50. |
- Varedian, Miranda, et al.
(författare)
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Interplaying factors for the formation of photoswitchable β-hairpins : The advantage of a flexible switch
- 2009
-
Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 15:2, s. 107-113
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Tidskriftsartikel (refereegranskat)abstract
- A series of peptidomimetics intended to promote the β-hairpin motif have been studied. Structural variations include a turn region with and without a photoswitchable chromophore, and strands with amino acid side chains supporting various degrees of interstrand interactions for hairpin stabilisation. The propensity of the compounds to form β-hairpinswas evaluated experimentally by NMR spectroscopy, translational self-diffusion studies and CD spectroscopy. In the presence of hairpin stabilising interstrand interactions, the structurally flexible stilbene chromophore appeared to be well compatible with the imposed secondary structure.
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