ISSN:1075-2617    

DOI:10.1002/psc.2783

年代:2015

数据来源: WILEY

摘要:

Host defense (antimicrobial) peptides, produced by all complex organisms, typically contain an abundance of positively charged and hydrophobic amino acid residues. A small synthetic peptide termed innate defense regulator (IDR‐)1018 was derived by substantial modification of the bovine neutrophil host defense peptide bactenecin. Here, we review its intriguing properties that include anti‐infective, anti‐inflammatory, wound healing, and anti‐biofilm activities. It was initially developed as an immune modulator with an ability to selectively enhance chemokine production and polarize cellular differentiation while suppressing/balancing the pro‐inflammatory response. In this regard, it has demonstratedin vivoactivity in murine models including enhancement of wound healing and an ability to protect againstStaphylococcus aureus, multidrug resistantMycobacterium tuberculosis, herpes virus, and inflammatory disorders, including cerebral malaria and neuronal damage in a pre‐term birth model. More recently, IDR‐1018 was shown, in a broad‐spectrum fashion, to selectively target bacterial biofilms, which are adaptively resistant to many antibiotics and represent the most common growth state of bacteria in human infections. Furthermore, IDR‐1018 demonstrated synergy with conventional antibiotics to both prevent biofilm formation and treat pre‐existing biofilms. These data are consistent with a strong potential as an adjunctive therapy against antibiotic‐resistant infections. Copyright © 2015 European Peptide Society an

ISSN:1075-2617    

DOI:10.1002/psc.2708

年代:2015

数据来源: WILEY

摘要:

The remarkable structural and chemical properties of adamantane afford attractive opportunities to design various adamantane‐based scaffolds for biomedical applications. A wide range of mono‐functionalized adamantane compounds have already been investigated and reviewed, mostly as anti‐viral agents. The four bridgehead positions of adamantane provide many possibilities to design poly‐functional derivatives, and the recent conception of adamantane building blocks with multiple substituents has shown promising applications in several domains. In this review, we provide a detailed description of the different ways to synthesize multifunctional derivatives starting from adamantane molecule as the main core. We will then describe the interesting biological activity of the diverse multivalent scaffolds, focusing in particular on peptide‐based systems. The results reported here will certainly encourage the development of novel adamantane‐based structures for biological purposes. Copyright © 2015 European Peptide Society and John Wil

ISSN:1075-2617    

DOI:10.1002/psc.2719

年代:2015

数据来源: WILEY

摘要:

Biophysical and structural studies of peptide–lipid interactions, peptide topology and dynamics have changed our view on how antimicrobial peptides insert and interact with membranes. Clearly, both the peptides and the lipids are highly dynamic, change and mutually adapt their conformation, membrane penetration and detailed morphology on a local and a global level. As a consequence, the peptides and lipids can form a wide variety of supramolecular assemblies in which the more hydrophobic sequences preferentially, but not exclusively, adopt transmembrane alignments and have the potential to form oligomeric structures similar to those suggested by the transmembrane helical bundle model. In contrast, charged amphipathic sequences tend to stay intercalated at the membrane interface where they cause pronounced disruptions of the phospholipid fatty acyl packing. At increasing local or global concentrations, the peptides result in transient membrane openings, rupture and ultimately lysis. Depending on peptide‐to‐lipid ratio, lipid composition and environmental factors (temperature, buffer composition, ionic strength, etc.), the same peptide sequence can result in a variety of those responses. Therefore, the SMART model has been introduced to cover the full range of possibilities. With such a view in mind, novel antimicrobial compounds have been designed from amphipathic polymers, peptide mimetics, combinations of ultra‐short polypeptides with hydrophobic anchors or small designer molecules. Copyright © 2015 European Peptide Society and John Wiley&S

ISSN:1075-2617    

DOI:10.1002/psc.2729

年代:2015

数据来源: WILEY

摘要:

Cell‐penetrating peptides (CPPs) are short sequences often rich in cationic residues with the remarkable ability to cross cell membranes. In the past 20 years, CPPs have gained wide interest and have found numerous applications in the delivery of bioactive cargoes to the cytosol and even the nucleus of living cells. The covalent or non‐covalent addition of hydrocarbon moieties to cationic CPPs alters the hydrophobicity/hydrophilicity balance in their sequence. Such perturbation dramatically influences their interaction with the cell membrane, might induce self‐assembling properties and modifies their intracellular trafficking. In particular, the introduction of lipophilic moieties changes the subcellular distribution of CPPs and might result in a dramatically increase of the internalization yield of the co‐transported cargoes. Herein, we offer an overview of different aspects of the recent findings concerning the properties of CPPs covalently or non‐covalently associated to hydrocarbons. We will focus on the impact of the hydrocarbon moieties on the delivery of various cargoes, either covalently or non‐covalently bound to the modified CPPs. We will also provide some key elements to rationalize the influence of the hydrocarbons moieties on the cellular uptake. Furthermore, the recentin vitroandin vivosuccessful applications of acylated CPPs will be summarized to provide a broad view of the versatility of these modified CPPs as small‐molecules and oligonucleotides vectors. Copyright © 2015 European Peptide Society and John

ISSN:1075-2617    

DOI:10.1002/psc.2755

年代:2015

数据来源: WILEY

摘要:

Synthetic peptides, representative of sequences related to the complementarity determining regions and constant region of antibodies, proved to exertin vitro,ex vivoand/orin vivoantimicrobial, antiviral, anti‐tumour and/or immunomodulatory activities, conceivably mediated by different mechanisms of action and regardless of the specificity and isotype of the belonging immunoglobulin. Antibody‐derived peptides can show intrinsic properties of self‐aggregation inβstructures, able to assemble on molecular targets and dissociate spontaneously, leading to the formation of hydrogels. Whilst the self‐assembled state may provide protection against proteases and the slow kinetic of dissociation assures a release of the active form over time, the receptor affinity is responsible for targeted delivery. Peptides derived from single amino acid substitution of bioactive antibody fragments, adopted as surrogates of natural point mutations, displayed further differential biological activities. Overall, these observations allow to envisage that antibodies could represent an unlimited source of new anti‐infective and anti‐tumour peptides. Copyright © 2015 European Peptide Society and John Wi

ISSN:1075-2617    

DOI:10.1002/psc.2748

年代:2015

数据来源: WILEY

摘要:

While it is now possible to identify and genetically fingerprint the causative agents of emerging viral diseases, often with extraordinary speed, suitable therapies cannot be developed with equivalent speed, because drug discovery requires information that goes beyond knowledge of the viral genome. Peptides, however, may represent a special opportunity.For all enveloped viruses, fusion between the viral and the target cell membrane is an obligatory step of the life cycle. Class I fusion proteins harbor regions with a repeating pattern of amino acids, the heptad repeats (HRs), that play a key role in fusion, and HR‐derived peptides such as enfuvirtide, in clinical use for HIV, can block the process. Because of their characteristic sequence pattern, HRs are easily identified in the genome by means of computer programs, providing the sequence of candidate peptide inhibitors directly from genomic information.Moreover, a simple chemical modification, the attachment of a cholesterol group, can dramatically increase the antiviral potency of HR‐derived inhibitors and simultaneously improve their pharmacokinetics. Further enhancement can be provided by dimerization of the cholesterol‐conjugated peptide. The examples reported so far include inhibitors of retroviruses, paramyxoviruses, orthomyxoviruses, henipaviruses, coronaviruses, and filoviruses. For some of these viruses,in vivoefficacy has been demonstrated in suitable animal models.The combination of bioinformatic lead identification and potency/pharmacokinetics improvement provided by cholesterol conjugation may form the basis for a rapid response strategy, where development of an emergency cholesterol‐conjugated therapeutic would immediately follow the availability of the genetic information of a new enveloped virus. Copyright © 2014 European Peptide Society and John Wiley&S

ISSN:1075-2617    

DOI:10.1002/psc.2706

年代:2015

数据来源: WILEY

摘要:

The solid‐phase synthesis of azapeptides possessing a C‐terminal aza‐residue has been accomplished by a protocol featuring regioselective alkylation of benzhydrylidene‐aza‐glycinamide and illustrated by the syntheses of [aza‐Lys6] growth‐hormone‐releasing peptide‐6 analogs. Copyright © 2015 European Peptide Society and Jo

ISSN:1075-2617    

DOI:10.1002/psc.2711

年代:2015

数据来源: WILEY

摘要:

The urotensin II receptor (UTR) has long been studied mainly for its involvement in the cardiovascular homeostasis both in health and disease state. Two endogenous ligands activate UTR, i.e. urotensin II (U‐II) and urotensin II‐related peptide (URP). Extensive expression of the two ligands uncovers the diversified pathophysiological effects mediated by the urotensinergic system such as cardiovascular disorders, smooth muscle cell proliferation, renal disease, diabetes, and tumour growth. As newly reported, U‐II and URP have distinct effects on transcriptional activity, cell proliferation, and myocardial contractile activities supporting the idea that U‐II and URP interact with UTR in a distinct manner (biased agonism). To shed light on the origin of the divergent activities of the two endogenous ligands, we performed a conformational study on URP by solution NMR in sodium dodecyl sulfate micelle solution and compared the obtained NMR structure of URP with that ofhU‐II previously determined. Finally, we undertook docking studies between URP,hU‐II, and an UT receptor model. Copyright © 2015 European Peptide Society and John Wil

ISSN:1075-2617    

DOI:10.1002/psc.2740

年代:2015

数据来源: WILEY

摘要:

Experimental vaccination to induce antibodies (Abs) capable of cytokine antagonism shows promise as a novel immunotherapy for chronic inflammatory disease. We prepared a hybrid antigen consisting of residues 141–235 of rat TNF‐α fused to the C‐terminus of glutathione‐S‐transferase (GST), chemically modified to incorporate aldehyde residues, for development of an auto‐vaccine eliciting anti‐rTNF‐α Abs. In rat immunization the soluble aldehyde‐modified fusion protein did not generate observable Ab responses. By contrast, vaccination with the aldehyde‐modified fusion protein adsorbed on alum induced anti‐TNF‐α autoAbs with high titer and neutralizing activity. Induction of adjuvant arthritis in rats pre‐immunized with unmodified fusion protein or a control protein in alum resulted in severe inflammation and joint damage, whereas the disease induced in rats immunized with the aldehyde‐bearing fusion protein in alum was markedly attenuated. Similar results were obtained in a collagen‐induced rat arthritis model. Anti‐collagen II IgG Ab titers did not deviate significantly in groups pre‐immunized with modified fusion protein and control protein, suggesting that anti‐TNF vaccination did not skew the immune response related to disease induction. This study demonstrates synergy between particulate alum and protein bound carbonyl residues for enhancement of protein immunogenicity. The antigen‐specific co‐adjuvant system could prove advantageous for breaking tolerance in emerging auto‐vaccination therapies targeting inflammatory cytokines as well as for enhancing a broader category of subunit vaccines. Aldehyde adduction introduces a minimal modification which, together with the established use of alum as a safe adjuvant for human use, could be favorable for further vaccine development. Copyright © 2014 Euro

ISSN:1075-2617    

DOI:10.1002/psc.2718

年代:2015

数据来源: WILEY