摘要:

Synthetic mimics of discontinuous epitopes may have a wide range of potential applications, including synthetic vaccines and inhibition of protein–protein interactions. However, synthetic access to these relatively complex peptide molecular constructs is limited. This paper describes a versatile convergent strategy for the construction of protein mimics presenting three different cyclic peptides. Using an orthogonal alkyne protection strategy, peptide loops were introduced successively onto a triazacyclophane scaffold via Cu(I)‐catalyzed azide alkyne cycloaddition. This method provides rapid access to protein mimics requiring different peptide segments for their interaction and activity. Copyright © 2014 European Peptide Society and John Wiley&Sons,

ISSN:1075-2617    

DOI:10.1002/psc.2624

年代:2014

数据来源: WILEY

摘要:

This study was concerned with the interaction between the cationic antimicrobial peptide, protamine (Ptm) and the cytoplasmic membranes of the gram‐negative bacteriaEscherichia coli, Salmonella typhimuriumandPseudomonas aeruginosa. The objective of the study was to explain the observed paradox of internalization without permanent disruption of the cell envelope. We carried out Monte Carlo computer simulation of Ptm in an aqueous environment in the presence of ~100 mM NaCl and model membranes consisting of either (65:35) or (75:25) PE:PG molar ratios. The (75:25) model, representative of the gram‐negative cytoplasmic membrane, showed that the Ptm center of mass remained at least 7 nm from the membrane surface leading to the prediction that Ptm would not internalize via disruption of the inner membrane.By using immunoelectron microscopy of Ptm‐treated cells, we showed that Ptm internalization to the cytoplasm took place rapidly in the presence or absence of the outer envelope. Ultrastructural examination revealed no obvious morphological changes to cells that were treated with subinhibitory or bactericidal levels of Ptm. Reconstituted phospholipid bilayers were constructed and were unperturbed by Ptm treatment over a wide range of concentrations and applied transmembrane voltages. We conclude that in the cases of the cell envelopes ofE. coli, S. typhimuriumandP. aeruginosa, Ptm internalized by means independent of the phospholipid bilayer, most likely mediated by one or more membrane proteins such as cation‐selective barrel‐like proteins. Work is currently underway to test this hypothesis. © 2014 The Authors.Journal of Peptide Sciencepublished by

ISSN:1075-2617    

DOI:10.1002/psc.2610

年代:2014

数据来源: WILEY

摘要:

Public health of human beings is threatened by superbugs. Novel human beta‐defensins, which contribute to host defense against pathogen invasion and innate immune protection, might be a potent natural candidate pool for new antibiotic lead screening. In the present work, we successfully expressed and purified a novel human beta‐defensin, DEFB120, using the IMPACT‐TWIN system inEscherichia coliand identified the purified homogeneous proteins using MALDI‐TOF mass spectrometry. Then, we performed the fundamental studies on the structure and biological functions for the DEFB120 peptide. The recombinant DEFB120 peptide showed wide antimicrobial effects againstE. coli,Staphylococcus aureusandCandida albicansstrains without significant hemolytic activity. Furthermore, the high lipopolysaccharide (LPS)‐binding affinityin vitroindicated that DEFB120 might be associated with the inhibition of LPS‐induced inflammatory response. These results may pave a way for exploiting the essential physiological functions of DEFB120 and also for the development of natural antibiotic pools. Copyright © 2014 European Peptide Society and John W

ISSN:1075-2617    

DOI:10.1002/psc.2611

年代:2014

数据来源: WILEY

摘要:

The ubiquitin–proteasome pathway (UPP) influences essential cellular functions including cell growth, differentiation, apoptosis, signal transduction, antigen processing and inflammatory responses. The main proteolytic component of the UPP is the 26S proteasome, which is responsible for the turnover of many cellular proteins and represents an attractive target for the treatment of pathologies such as cancer, as well as inflammatory, immune and neurodegenerative diseases. Natural and synthetic proteasome inhibitors having different chemical structures and potency have been discovered. We report herein the synthesis, proteasome inhibition and modelling studies of novel C‐terminal isoxazoline vinyl ester pseudopeptides. Some new compounds that contain a C‐terminal extended conjugation inhibitβ1 and especiallyβ5 proteasomal catalytic subunits with IC50values ranging from 10 to 100 µm. These results will permit further optimization based on these structural moieties to develop more active and selective molecules. Copyright © 2014 European Peptide Society and John Wile

ISSN:1075-2617    

DOI:10.1002/psc.2612

年代:2014

数据来源: WILEY

摘要:

A range of inorganic and organoelement halides was evaluated as acidic promoters of direct Nin‐formylation of tryptophan. In addition to Me3SiBr, the less expensive PBr3was found to be highly efficient and was selected for further optimization. A convenient and reproducible synthetic procedure for Nin‐formyltryptophan hydrobromide developed in this way was scaled to 150 mmol and successfully extended to some derivatives of Trp and closely related indoles as detailed in the present paper. The scope of the method seems to be restricted to indoles substituted at C‐3. Copyright © 2014 European Peptide Society and John Wiley&S

ISSN:1075-2617    

DOI:10.1002/psc.2613

年代:2014

数据来源: WILEY

摘要:

CXCR4 is a G‐protein‐coupled receptor involved in a number of physiological processes in the hematopoietic and immune systems. CXCL12/CXCR4 axis plays a central role in diseases, such as HIV, cancer, WHIM syndrome, rheumatoid arthritis, pulmonary fibrosis, and lupus and, hence, indicated as putative therapeutic target. Although multiple CXCR4 antagonists have been developed, there is only one marketed drug, plerixafor, indicated for stem cell mobilization in poor mobilizer patients. In this work, we have designed and synthesized two peptides, six and seven residues long, using as template the N‐terminal region of CXCL12; analyzed their conformations by CD, NMR, and molecular dynamics simulations; simulated their complexes with CXCR4 by docking methods; and validated these data byin vitrostudies. The results showed that the two peptides are rather flexible in aqueous solution lacking ordered secondary structure elements and present a promising affinity for CXCR4. This affinity is not revealed for CXCR7, indicating a specificity for CXCR4. Copyright © 2014 European Peptide Society and John Wiley&Son

ISSN:1075-2617    

DOI:10.1002/psc.2614

年代:2014

数据来源: WILEY

摘要:

We have in the present study explored the anticancer activity against human Burkitt's lymphoma cells (Ramos) of a series of small linear and cyclic tetrapeptides containing aβ2,2‐amino acid with either two 2‐naphthyl‐methylene or twopara‐CF3‐benzyl side chains, along with their interaction with the main plasma protein human serum albumin (HSA). The cyclic and more amphipathic tetrapeptides revealed a notably higher anticancer potency against Ramos cells [50% inhibitory concentration (IC50) 11–70 μM] compared to the linear tetrapeptide counterparts (IC5018.7 to>413 μM). The most potent cyclic tetrapeptide c3 had a 16.5‐fold preference for Ramos cells compared to human red blood cells, whereas the cyclic tetrapeptide c1 both showed low hemolytic activity and displayed the overall highest (2.9‐fold) preference for Ramos cells (IC5023 μM) compared to healthy human lung fibroblast cells (MRC‐5). Investigating the interaction of selected tetrapeptides and recently reported hexapeptides with HSA revealed that the peptides bind to drug site II of HSA in the 22–28 μM range, disregarding size and overall structure. NMR andin silicomolecular docking experiments identified the lipophilic residues as responsible for the interaction, butin vitrostudies showed that the anticancer potency of the peptides varied in the presence of HSA and that c3 remained the most potent peptide. Based on our findings, we call for implementing serum albumin binding in development of anticancer peptides, as it may have implications for future administration and systemic distribution of peptide‐based cancer drugs. Copyright © 2014 European Pepti

ISSN:1075-2617    

DOI:10.1002/psc.2615

年代:2014

数据来源: WILEY

摘要:

The influenza fusion peptide located at the N‐terminus of the hemagglutinin HA2 subunit initiates the fusing process of the viral membrane with the host cell endosomal membrane. It had been reported that the structure of a 20‐residue H3 subtype fusion peptide (H3‐HAfp20) was significantly different with that of a H1 subtype 23‐residue one (H1‐HAfp23). The sequential difference between the 12th and 15th residues of H1 and H3 subtypes could not fully explain the conformational variation. The first and last three amino acids of H3‐HAfp23 involved in formation of hydrogen bonds may play an important role in fusion process. To confirm this hypothesis, we investigate the structures of H3‐HAfp23 peptide and its mutants, G1S and G1V, in dodecylphosphatidyl choline micelles by using heteronuclear NMR technology. The results demonstrate that, similar to H1‐HAfp23 but significantly different with H3‐HAfp20, H3‐HAfp23 also has tight helical hairpin structure with the N‐ and C‐terminuses linked together because of the hydrogen bonds between Gly1and the last three amino acids, Trp21―Tyr22―Gly23. Although the ‘hemifusion’ G1S and lethal G1V mutants have hairpin‐like helical structures, the distances between the N‐ and C‐terminuses are increased as shortage of the hydrogen bonds and the larger kink angle between the antiparallel helices. The paramagnetic ion titration experiments show that the terminuses are inserted into the dodecylphosphatidyl choline micelles used as solving media. These may imply that the tight helical hairpin structure, especially the closed conformation at terminus, plays an important role in fusion activity. Copyright © 2014 European Pe

ISSN:1075-2617    

DOI:10.1002/psc.2616

年代:2014

数据来源: WILEY

ISSN:1075-2617    

DOI:10.1002/psc.2559

年代:2014

数据来源: WILEY