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Constrained peptide

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https://www.readbyqxmd.com/read/28107435/peptide-targeted-by-human-antibodies-associated-with-hiv-vaccine-associated-protection-assumes-a-dynamic-%C3%AE-helical-structure
#1
Mohammed S Aiyegbo, Evgeny Shmelkov, Lorenzo Dominguez, Michael Goger, Shibani Battacharya, Allan C deCamp, Peter B Gilbert, Phillip W Berman, Timothy Cardozo
The only evidence of vaccine-induced protection from HIV acquisition in humans was obtained in the RV144 HIV vaccine clinical trial. One immune correlate of risk in RV144 was observed to be higher titers of vaccine-induced antibodies (Abs) reacting with a 23-mer non-glycosylated peptide with the same amino acid sequence as a segment in the second variable (V2) loop of the MN strain of HIV. We used NMR to analyze the dynamic 3D structure of this peptide. Distance restraints between spatially proximate inter-residue protons were calculated from NOE cross peak intensities and used to constrain a thorough search of all possible conformations of the peptide...
2017: PloS One
https://www.readbyqxmd.com/read/28105269/electrophilic-helical-peptides-that-bond-covalently-irreversibly-and-selectively-in-a-protein-protein-interaction-site
#2
Aline Dantas de Araujo, Junxian Lim, Andrew C Good, Renato T Skerlj, David P Fairlie
Protein-protein interactions mediate most physiological and disease processes. Helix-constrained peptides potently mimic or inhibit these interactions by making multiple contacts over large surface areas. However, despite high affinities, they typically have short lifetimes bound to the protein. Here we insert both a helix-inducing constraint and an adjacent electrophile into the native peptide ligand BIM to target the oncogenic protein Bcl2A1. The modified BIM peptide bonds covalently and irreversibly to one cysteine within the helix-binding groove of Bcl2A1, but not to two other exposed cysteines on its surface, and shows no covalent bonding to other Bcl2 proteins...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28059508/non-classical-size-dependence-of-permeation-defines-bounds-for-passive-adsorption-of-large-drug-molecules
#3
Cameron R Pye, William M Hewitt, Joshua A Schwochert, Terra D Haddad, Chad E Townsend, Lyns Etienne, Yongtong Lao, Chris Limberakis, Akihiro Furukawa, Alan M Mathiowetz, David A Price, Spiros Liras, R Scott Lokey
There is a growing number of intracellular protein-protein interactions (PPI's) with potential therapeutic importance that demand larger ligands than those that neatly fit into most common criteria for "drug-likeness". Macrocyclic peptides pro-vide the large surface area required to inhibit PPIs and, in principle, avoid many of the pitfalls associated with peptides, including low stability and membrane permeability. However, the design of passively cell-permeable molecules in this space remains a great challenge due to the poorly understood roles of molecular size and lipophilicity in determining pas-sive membrane permeability above MW ~500...
January 6, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28054413/the-importance-of-being-aib-aggregation-and-self-assembly-studies-on-conformationally-constrained-oligopeptides
#4
Mariano Venanzi, Emanuela Gatto, Fernando Formaggio, Claudio Toniolo
The role of the conformationally constrained α-aminoisobutyric acid (Aib) residue in the aggregation and self-assembly properties of oligopeptides is discussed, critically reviewing our recent work in the field. In this connection, three significant case studies are presented: (i) aggregation propensity of Aib homo-oligopeptides of different length; (ii) perturbation of the conformational and aggregation properties of Ala-based pentapeptides by a single Aib versus Ala substitution; and (iii) build up of self-assembled monolayers formed by Aib homo-hexapeptide building blocks...
January 5, 2017: Journal of Peptide Science: An Official Publication of the European Peptide Society
https://www.readbyqxmd.com/read/28035784/enhancing-the-cell-permeability-and-metabolic-stability-of-peptidyl-drugs-by-reversible-bicyclization
#5
Ziqing Qian, Curran A Rhodes, Lucas C McCroskey, Jin Wen, George Appiah-Kubi, David J Wang, Denis C Guttridge, Dehua Pei
Therapeutic applications of peptides are currently limited by their proteolytic instability and impermeability to the cell membrane. A general, reversible bicyclization strategy is now reported to increase both the proteolytic stability and cell permeability of peptidyl drugs. A peptide drug is fused with a short cell-penetrating motif and converted into a conformationally constrained bicyclic structure through the formation of a pair of disulfide bonds. The resulting bicyclic peptide has greatly enhanced proteolytic stability as well as cell-permeability...
December 30, 2016: Angewandte Chemie
https://www.readbyqxmd.com/read/28004737/investigating-the-neuroprotective-effects-of-turmeric-extract-structural-interactions-of-%C3%AE-amyloid-peptide-with-single-curcuminoids
#6
Rosario Randino, Manuela Grimaldi, Marco Persico, Augusta De Santis, Elena Cini, Walter Cabri, Antonella Riva, Gerardino D'Errico, Caterina Fattorusso, Anna Maria D'Ursi, Manuela Rodriquez
A broad biophysical analysis was performed to investigate the molecular basis of the neuroprotective action of Curcuma longa extracts in Alzheimer's disease. By combining circular dichroism and electron paramagnetic resonance experiments with molecular modeling calculations, the minor components of Curcuma longa extracts, such as demethoxycurcumin (2, DMC), bisdemethoxycurcumin (3, BDMC) and cyclocurcumin (4, CYC), were analyzed in a membrane environment mimicking the phospholipid bilayer. Our study provides the first evidence on the relative role of single curcuminoids interacting with Aβ-peptide...
December 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/28004569/strategies-for-the-activation-and-release-of-the-membranolytic-peptide-melittin-from-liposomes-using-endosomal-ph-as-a-trigger
#7
Erik Oude Blenke, Malgorzata Sleszynska, Martijn Evers, Gert Storm, Nathaniel I Martin, Enrico Mastrobattista
Endosomolytic peptides are often coupled to drug delivery systems to enhance endosomal escape, which is crucial for the delivery of macromolecular drugs that are vulnerable to degradation in the endolysosomal pathway. Melittin is a 26 amino acid peptide derived from bee venom that has a very high membranolytic activity. However, such lytic peptides also impose a significant safety risk when applied in vivo as they often have similar activity against red blood cells and other non-target cell membranes. Our aim is to control the membrane-disrupting capacity of these peptides in time and space by physically constraining them to a nanocarrier surface in such a way that they only become activated when delivered inside acidic endosomes...
December 22, 2016: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28000361/cyclopropane-based-peptidomimetics-mimicking-wide-ranging-secondary-structures-of-peptides-conformational-analysis-and-their-use-in-rational-ligand-optimization
#8
Akira Mizuno, Tomoshi Kameda, Tomoki Kuwahara, Hideyuki Endoh, Yoshihiko Ito, Shizuo Yamada, Kimiko Hasegawa, Akihito Yamano, Mizuki Watanabe, Mitsuhiro Arisawa, Satoshi Shuto
Detailed conformational analyses of our previously reported cyclopropane-based peptidomimetics and conformational analysis-driven ligand optimization are described. Computational calculations and X-ray crystallography showed that the characteristic features of cyclopropane function effectively to constrain the molecular conformation in a three-dimensionally diverse manner. Subsequent principal component analysis revealed that the diversity covers the broad chemical space filled by peptide secondary structures in terms of both main-chain and side-chain conformations...
December 21, 2016: Chemistry: a European Journal
https://www.readbyqxmd.com/read/27995801/molecular-dynamics-study-of-nitrogen-pyramidalized-bicyclic-%C3%AE-proline-oligomers-length-dependent-convergence-to-organized-structures
#9
Yuko Otani, Satoshi Watanabe, Tomohiko Ohwada, Akio Kitao
In this study, the solution structures of the homooligomers of a conformationally constrained bicyclic proline-type β-amino acid were studied by means of molecular dynamics (MD) calculations in explicit methanol and water using the umbrella sampling method. The ratio of trans-amide and cis-amide was estimated by NMR and the rotational barrier of the amide of acetylated bicyclic amino acid monomer was estimated by two-dimensional (2D) exchange spectroscopy (EXSY) or line-shape analysis. A bias potential was introduced with respect to the amide torsion angle ω to enhance conformational exchange including isomerization of amide bonds by lowering the rotation energy barrier...
December 20, 2016: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/27974608/rapid-synthesis-of-cyclic-oligomeric-depsipeptides-with-positional-stereochemical-and-macrocycle-size-distribution-control
#10
Suzanne M Batiste, Jeffrey N Johnston
Macrocyclic small molecules are attractive tools in the development of sensors, new materials, and therapeutics. Within early-stage drug discovery, they are increasingly sought for their potential to interact with broad surfaces of peptidic receptors rather than within their narrow folds and pockets. Cyclization of linear small molecule precursors is a straightforward strategy to constrain conformationally mobile motifs, but forging a macrocycle bond typically becomes more difficult at larger ring sizes. We report the development of a general approach to discrete collections of oligomeric macrocyclic depsipeptides using an oligomerization/macrocyclization process governed by a series of Mitsunobu reactions of hydroxy acid monomers...
December 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27964762/new-tools-to-analyze-overlapping-coding-regions
#11
Amir H Bayegan, Juan Antonio Garcia-Martin, Peter Clote
BACKGROUND: Retroviruses transcribe messenger RNA for the overlapping Gag and Gag-Pol polyproteins, by using a programmed -1 ribosomal frameshift which requires a slippery sequence and an immediate downstream stem-loop secondary structure, together called frameshift stimulating signal (FSS). It follows that the molecular evolution of this genomic region of HIV-1 is highly constrained, since the retroviral genome must contain a slippery sequence (sequence constraint), code appropriate peptides in reading frames 0 and 1 (coding requirements), and form a thermodynamically stable stem-loop secondary structure (structure requirement)...
December 13, 2016: BMC Bioinformatics
https://www.readbyqxmd.com/read/27939012/immunofocusing-using-conformationally-constrained-v3-peptide-immunogens-improves-hiv-1-neutralization
#12
Adi Moseri, Eshu Sinha, Henni Zommer, Boris Arshava, Fred Naider, Jacob Anglister
V3-directed antibodies are present in practically all HIV-1 infected patients and in individuals vaccinated with gp120. The levels of maternal V3-directed antibodies were recently shown to correlate with reduced mother to child transmission, and V3 IgGs were found to be a negative correlate of risk in the RV-144 human trial. mAb directed to the tip of the V3 are capable of broad neutralization of Tier-1 and some Tier-2 viruses. Here we report an immunofocusing approach using conformationally constrained V3 peptides of different lengths...
January 5, 2017: Vaccine
https://www.readbyqxmd.com/read/27924557/high-throughput-analysis-of-mammalian-receptor-tyrosine-kinase-activation-in-yeast-cells
#13
Nobuo Yoshimoto, Shun'ichi Kuroda
Tyrosine phosphorylation is an essential posttranslational modification in intracellular signaling molecules. Since tyrosine phosphorylation occurs in less than 0.1 % of all phosphorylated amino acids in mammalian cells, it is difficult to detect the nascent phosphotyrosine at a high signal-to-noise ratio due to high intracellular backgrounds (i.e., unexpected crosstalks among endogenous signaling molecules). In order to address this issue, we reconstituted the mammalian signaling pathway involving an extracellular ligand and a receptor tyrosine kinase (RTK) in Saccharomyces cerevisiae, a lower eukaryote that lacks endogenous tyrosine kinases...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27919612/an-in-tether-sulfoxide-chiral-center-influences-the-biophysical-properties-of-the-n-capped-peptides
#14
Jingxu Li, Yuan Tian, Dongyuan Wang, Yujie Wu, Xiyang Ye, Zigang Li
Thanks to their large binding interfaces, peptides are attractive ligands targeting protein-protein interactions compared with small molecules. Various strategies to improve peptides' pharmaceutical properties have been developed to constrain peptides into their functional three-dimensional structures. In our previous work, we reported that an in-tether chiral center could modulate peptides' biophysical properties. Herein, we applied this concept to construct a chiral sulfoxide center into the N-terminal end-cap system...
November 25, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27918136/development-of-cell-permeable-non-helical-constrained-peptides-to-target-a-key-protein-protein-interaction-in-ovarian-cancer
#15
Mareike M Wiedmann, Yaw Sing Tan, Yuteng Wu, Shintaro Aibara, Wenshu Xu, Hannah F Sore, Chandra S Verma, Laura Itzhaki, Murray Stewart, James D Brenton, David R Spring
There is a lack of current treatment options for ovarian clear cell carcinoma (CCC) and the cancer is often resistant to platinum-based chemotherapy. Hence there is an urgent need for novel therapeutics. The transcription factor hepatocyte nuclear factor 1β (HNF1β) is ubiquitously overexpressed in CCC and is seen as an attractive therapeutic target. This was validated through shRNA-mediated knockdown of the target protein, HNF1β, in five high- and low-HNF1β-expressing CCC lines. To inhibit the protein function, cell-permeable, non-helical constrained proteomimetics to target the HNF1β-importin α protein-protein interaction were designed, guided by X-ray crystallographic data and molecular dynamics simulations...
January 9, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/27904012/new-trends-in-drug-discovery-and-development-by-constrained-peptides
#16
Keiichi Masuya
No abstract text is available yet for this article.
2016: Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica
https://www.readbyqxmd.com/read/27879976/correction-downsizing-the-bad-bh3-peptide-to-small-constrained-%C3%AE-helices-with-improved-ligand-efficiency
#17
Nicholas E Shepherd, Rosemary S Harrison, Gloria Ruiz-Gomez, Giovanni Abbenante, Jody M Mason, David P Fairlie
Correction for 'Downsizing the BAD BH3 peptide to small constrained α-helices with improved ligand efficiency' by Nicholas E. Shepherd et al., Org. Biomol. Chem., 2016, DOI: 10.1039/c6ob02185a.
December 28, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27865644/bioactivity-of-topologically-confined-gramicidin-a-dimers
#18
Kirtikumar B Jadhav, Claudia Stein, Oliwia Makarewicz, Gabriele Pradel, Roman J Lichtenecker, Holger Sack, Stefan H Heinemann, Hans-Dieter Arndt
The d-/l-peptide gramicidin A (gA) is well known as a pivotal ion channel model and shows a broad spectrum of bioactivities such as antibiosis, antimalarial activity, as well as hemolysis. We applied inter-chain disulfide bonds to constrain the conformational freedom of gA into parallel and antiparallel dimeric topologies. Albeit the constructs were not found to be monoconformational, CD- and IR-spectroscopic studies suggested that this strategy indeed restricted the conformational space of the d-/l-peptide construct, and that β-helical secondary structures prevail...
January 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27819377/downsizing-the-bad-bh3-peptide-to-small-constrained-%C3%AE-helices-with-improved-ligand-efficiency
#19
Nicholas E Shepherd, Rosemary S Harrison, Gloria Ruiz-Gomez, Giovanni Abbenante, Jody M Mason, David P Fairlie
Bcl2 Homology (BH) proteins can either trigger or prevent programmed cell death or apoptosis. Deregulation of the BH protein family network leads to evasion of apoptosis, uncontrolled proliferation and is a hallmark of cancer. Inhibition of pro-survival BH proteins is a promising chemotherapeutic strategy for certain cancers. We have examined whether helix-constrained peptides based on the BAD BH3 domain (residues 103-127) can be downsized to much smaller more drug-like peptides. We report the preparation, structural characterisation, in vitro Bcl-xL inhibition and leukemic T-cell killing ability of 45 linear, mono-, bi- and tricyclic helical peptidomimetics between 8- and 19-residues in length...
November 7, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27812920/signatures-of-mechanically-interlocked-topology-of-lasso-peptides-by-ion-mobility-mass-spectrometry-lessons-from-a-collection-of-representatives
#20
Kevin Jeanne Dit Fouque, Hélène Lavanant, Séverine Zirah, Julian D Hegemann, Marcel Zimmermann, Mohamed A Marahiel, Sylvie Rebuffat, Carlos Afonso
Lasso peptides are characterized by a mechanically interlocked structure, where the C-terminal tail of the peptide is threaded and trapped within an N-terminal macrolactam ring. Their compact and stable structures have a significant impact on their biological and physical properties and make them highly interesting for drug development. Ion mobility - mass spectrometry (IM-MS) has shown to be effective to discriminate the lasso topology from their corresponding branched-cyclic topoisomers in which the C-terminal tail is unthreaded...
November 3, 2016: Journal of the American Society for Mass Spectrometry
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