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51.
Philip J. Kuehl Tracey Boyden Dan E. Dobry Melanie Doyle-Eisele Dwayne T. Friesen Jacob D. McDonald 《Drug development and industrial pharmacy》2016,42(1):150-156
Objective: Peptide YY3–36 [PYY(3–36)] has shown efficacy in appetite suppression when dosed by injection modalities (intraperitoneal (IP)/subcutaneous). Transitioning to needle-free delivery, towards inhalation, often utilizes systemic pharmacokinetics as a key endpoint to compare different delivery methods and doses. Systemic pharmacokinetics were evaluated for PYY3–36 when delivered by IP, subcutaneous, and inhalation, the systemic pharmacokinetics were then used to select doses in an appetite suppression pharmacodynamic study.Methods: Dry-powder formulations were manufactured by spray drying and delivered to mice via nose only inhalation. The systemic plasma, lung tissue, and bronchoalveolar lavage fluid pharmacokinetics of different inhalation doses of PYY(3–36) were compared to IP and subcutaneous efficacious doses. Based on these pharmacokinetic data, inhalation doses of 70:30 PYY(3–36):Dextran T10 were evaluated in a mouse model of appetite suppression and compared to IP and subcutaneous data.Results: Inhalation pharmacokinetic studies showed that plasma exposure was similar for a 2?×?higher inhalation dose when compared to subcutaneous and IP delivery. Inhalation doses of 0.22 and 0.65?mg/kg were for efficacy studies. The results showed a dose-dependent (not dose proportional) decrease in food consumption over 4?h, which is similar to IP and subcutaneous delivery routes.Conclusions: The pharmacokinetic and pharmacodynamics results substantiate the ability of pharmacokinetic data to inform pharmacodynamics dose selection for inhalation delivery of the peptide PYY(3–36). Additionally, engineered PYY(3–36):Dextran T10 particles delivered to the respiratory tract show promise as a non-invasive therapeutic for appetite suppression. 相似文献
52.
Dnyaneshwar B. Rasale Apurba K. Das 《International journal of molecular sciences》2015,16(5):10797-10820
Fabrication of self-assembled nanostructures is one of the important aspects in nanoscience and nanotechnology. The study of self-assembled soft materials remains an area of interest due to their potential applications in biomedicine. The versatile properties of soft materials can be tuned using a bottom up approach of small molecules. Peptide based self-assembly has significant impact in biology because of its unique features such as biocompatibility, straight peptide chain and the presence of different side chain functionality. These unique features explore peptides in various self-assembly process. In this review, we briefly introduce chemical reaction-mediated peptide self-assembly. Herein, we have emphasised enzymes, native chemical ligation and photochemical reactions in the exploration of peptide self-assembly. 相似文献
53.
Nature utilizes both order and disorder (or controlled disorder) to achieve exceptional materials properties and functions, while synthetic supramolecular materials mostly exploit just supramolecular order, thus limiting the structural diversity, responsiveness and consequent adaptive functions that can be accessed. Herein, we review the emerging field of supramolecular biomaterials where disorder and order deliberately co-exist, and can be dynamically regulated by considering both entropic and enthalpic factors in design. We focus on sequence-structure relationships that govern the (cooperative) assembly pathways of protein and peptide building blocks in these materials. Increasingly, there is an interest in introducing dynamic features in protein and peptide-based structures, such as the remarkable thermo-responsiveness and exceptional mechanical properties of elastin materials. Simultaneously, advances in the field of intrinsically disordered proteins (IDPs) give new insights about their involvement in intracellular liquid-liquid phase separation and formation of disordered, dynamic coacervate structures. These have inspired efforts to design biomaterials with similar dynamic properties. These hybrid ordered/disordered materials employ a combination of intramolecular and supramolecular order/disorder features for construction of assemblies that are dynamically reconfigurable. The assembly of these dynamic structures is mainly entropy-driven, relying on electrostatic and hydrophobic interactions and is mediated in part through the adopted (unstructured) protein conformation or by introducing an oppositely charged guest for peptide building blocks. Examples include design of protein building blocks composed of disordered repeat sequences of elastin-like polypeptides in combination with ordered regions that adopt a secondary structure, the co-assembly of proteins with peptide amphiphiles to achieve reconfigurable, yet highly stable membranes or tyrosine-containing tripeptides with sequence-controlled order/disorder that upon enzymatic oxidation give rise to melanin-like polymeric pigments with customizable properties. The resulting hybrid materials with controlled disorder can be metastable, and sensitive to various external stimuli giving rise to insights that are especially attractive for the design of responsive and adaptive materials. 相似文献
54.
《Food Control》2016
Previously, we have isolated a novel bacteriocin, peptide F1 from Tibetan Kefir, and demonstrated its superior antimicrobial activity. However, its antimicrobial mechanism is still undefined. This study was aimed to elucidate the antimicrobial mechanism of peptide F1 against Staphylococcus aureus. The antimicrobial effects of peptide F1 were characterized by the following methods: chemical assay to quantify cytoplasmic β-galactosidase leakage, atomic absorption spectrometry to measure the released potassium ions, transmission electron microscopy to visualize the cellular morphological changes, and electrophoresis analysis and atomic force microscopy together to exam the DNA binding activity. Our results revealed that peptide F1 exerted its bactericidal effects by damaging bacterial cell membranes and by binding to the genomic DNA in the cytoplasm, which both led to rapid cell death. 相似文献
55.
Dr. Gerbrand J. van der Heden van Noort Cami Talavera Ormeño Duco van Dalen Prof. Dr. Huib Ovaa 《Chembiochem : a European journal of chemical biology》2019,20(1):62-65
The enzyme-mediated construction of poly-ubiquitin (Ub) chains on target proteins leads to a variety of cellular responses and is involved in processes ranging from protein degradation to cell cycle control and immune responses. This complex post-translational modification system is under intense investigation, but generation of specific Ub chains and tools made thereof is not always trivial. We discovered that native methionine-1-linked polymeric ubiquitin chains can be constructed in a single chemical reaction. We validate correct folding and regioselective attachment of such chains using linkage specific proteases and further demonstrate that these poly-Ub chains can be converted into thioesters by the activating E1-enzyme. Subsequent ligation reactions using these in situ prepared thioesters leads to poly-ubiquitinated peptides. 相似文献
56.
57.
Yanping Sun Hui Liu Haonan Xing Lang Lang Lin Cheng Tianzhi Yang Li Yang Pingtian Ding 《Polymer International》2019,68(3):447-455
Histamine (HIS) can facilitate the endosomal escape of polyplexes via the ‘proton sponge effect’ because of its imidazole groups. Agmatine (AGM) can improve the transmembrane process of polyplexes as a result of its guanidinium groups. Therefore, HIS and AGM were used as amino monomers to react with cystamine bisacrylamide (CBA) through Michael addition. The synthesized peptide‐mimicking poly(CBA‐HIS/AGM)s showed high transfection efficiency and low cytotoxicity, indicating their great potential as gene carriers. The results also demonstrated that the effects of HIS and AGM on the properties of poly(CBA‐HIS/AGM)s were different: HIS could increase their buffering capacities and bioreducibility, but AGM could facilitate their plasmid DNA packaging and condensing abilities. In addition, the results of transfection mechanism studies indicated that poly(CBA‐HIS/AGM) polyplexes entered into cells mainly via clathrin‐dependent endocytosis and they could efficiently escape the endosome, indicating endosomal escape was not the limiting step for gene delivery based on these polymers. © 2018 Society of Chemical Industry 相似文献
58.
Hongxi Wu Yalan Liu Mingrong Guo Jingli Xie XiaMin Jiang 《Journal of food science》2014,79(9):C1635-C1642
Natural small peptides from foods have been proven to be efficient inhibitors of Angiotensin I–converting enzyme (ACE) for the regulation of blood pressure. The traditional ACE inhibitory peptides screening method is both time consuming and money costing, to the contrary, virtual screening method by computation can break these limitations. We establish a virtual screening method to obtain ACE inhibitory peptides with the help of Libdock module of Discovery Studio 3.5 software. A significant relationship between Libdock score and experimental IC50 was found, Libdock score = 10.063 log(1/IC50) + 68.08 (R2 = 0.62). The credibility of the relationship was confirmed by testing the coincidence of the estimated log(1/IC50) and measured log(1/IC50) (IC50 is 50% inhibitory concentration toward ACE, in μmol/L) of 5 synthetic ACE inhibitory peptides, which was virtual hydrolyzed and screened from a kind of seafood, Phascolosoma esculenta. Accordingly, Libdock method is a valid IC50 estimation tool and virtual screening method for small ACE inhibitory peptides. 相似文献
59.
The treatment of many diseases may require drugs that are capable to attack multiple targets simultaneously. Obviously, the virtual screening of multi-target drug candidates is much more time consuming compared to the single-target case. This, in particular, concerns the last step of virtual screening where the binding free energy is computed by conventional molecular dynamics simulation. To overcome this difficulty we propose a simple protocol which is relied on the fast steered molecular dynamics simulation and on available experimental data on binding affinity of reference ligand to a given target. Namely, first we compute non-equilibrium works generated during pulling ligands from the binding site using the steered molecular dynamics method. Then as top leads we choose only those compounds that have the non-equilibrium work larger than that of a reference compound for which the binding free energy has been already known from experiment.Despite many efforts no cures for AD (Alzheimer’s disease) have been found. One of possible reasons for this failure is that drug candidates were developed for a single target, while there are exist many possible pathways to AD. Applying our new protocol to five targets including amyloid beta fibril, peroxisome proliferator-activated receptor γ, retinoic X receptor α, β- and γ-secretases, we have found two potential drugs (CID 16040294 and CID 9998128) for AD from the large PubChem database. We have also shown that these two ligands can interfere with the activity of popular Acetylcholinesterase target through strong binding towards it. 相似文献
60.