| 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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| 8. |
- 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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| 9. |
- 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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| 10. |
- 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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