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https://www.readbyqxmd.com/read/28636317/downsizing-proto-oncogene-cfos-to-short-helix-constrained-peptides-that-bind-jun
#1
Daniel Baxter, Samuel R Perry, Timothy A Hill, W Mei Kok, Nathan R Zaccai, R Leo Brady, David P Fairlie, Jody M Mason
The oncogenic transcription factor activator protein-1 (AP-1) is a DNA-binding protein that assembles through dimerization of Fos and Jun protein subunits, their leucine-rich helical sequences entwining into a coiled-coil structure. This study reports on downsizing the proto-oncogene cFos protein (380 residues) to shorter peptides (37-25 residues) modified with helix-inducing constraints to enhance binding to Jun. A crystal structure is reported for a 37-residue Fos-derived peptide (FosW) bound to Jun. This guided iterative downsizing of FosW to shorter peptide sequences that were constrained into stable water-soluble α-helices by connecting amino acid side chains to form cyclic pentapeptide components...
June 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28630351/evolutionary-radiation-of-lanthipeptides-in-marine-cyanobacteria
#2
Andres Cubillos-Ruiz, Jessie W Berta-Thompson, Jamie W Becker, Wilfred A van der Donk, Sallie W Chisholm
Lanthipeptides are ribosomally derived peptide secondary metabolites that undergo extensive posttranslational modification. Prochlorosins are a group of lanthipeptides produced by certain strains of the ubiquitous marine picocyanobacteria Prochlorococcus and Synechococcus Unlike other lanthipeptide-producing bacteria, picocyanobacteria use an unprecedented mechanism of substrate promiscuity for the production of numerous and diverse lanthipeptides using a single lanthionine synthetase. Through a cross-scale analysis of prochlorosin biosynthesis genes-from genomes to oceanic populations-we show that marine picocyanobacteria have the collective capacity to encode thousands of different cyclic peptides, few of which would display similar ring topologies...
June 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28626832/fragment-binding-to-%C3%AE-secretase-1-without-catalytic-aspartate-interactions-identified-via-orthogonal-screening-approaches
#3
Frederik J R Rombouts, Richard Alexander, Erna Cleiren, Alex De Groot, Michel Carpentier, Joyce Dijkmans, Katleen Fierens, Stefan Masure, Diederik Moechars, Martina Palomino-Schätzlein, Antonio Pineda-Lucena, Andrés A Trabanco, Daan Van Glabbeek, Ann Vos, Gary Tresadern
An approach to identify β-secretase 1 (BACE1) fragment binders that do not interact with the catalytic aspartate dyad is presented. A ThermoFluor (thermal shift) and a fluorescence resonance energy transfer enzymatic screen on the soluble domain of BACE1, together with a surface plasmon resonance (SPR) screen on the soluble domain of BACE1 and a mutant of one catalytic Asp (D32N), were run in parallel. Fragments that were active in at least two of these assays were further confirmed using one-dimensional NMR (WaterLOGSY) and SPR binding competition studies with peptidic inhibitor OM99-2...
February 28, 2017: ACS Omega
https://www.readbyqxmd.com/read/28598597/azapeptide-synthesis-methods-for-expanding-side-chain-diversity-for-biomedical-applications
#4
Ramesh Chingle, Caroline Proulx, William D Lubell
Mimicry of bioactive conformations is critical for peptide-based medicinal chemistry because such peptidomimetics may augment stability, enhance affinity, and increase specificity. Azapeptides are peptidomimetics in which the α-carbon(s) of one or more amino acid residues are substituted by nitrogen. The resulting semicarbazide analogues have been shown to reinforce β-turn conformation through the combination of lone pair-lone pair repulsion of the adjacent hydrazine nitrogen and urea planarity. Substitution of a semicarbazide for an amino amide residue in a peptide may retain biological activity and add benefits such as improved metabolic stability...
June 9, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28580915/the-potential-use-of-single-particle-electron-microscopy-as-a-tool-for-structure-based-inhibitor-design
#5
S Rawson, M J McPhillie, R M Johnson, C W G Fishwick, S P Muench
Recent developments in electron microscopy (EM) have led to a step change in our ability to solve the structures of previously intractable systems, especially membrane proteins and large protein complexes. This has provided new opportunities in the field of structure-based drug design, with a number of high-profile publications resolving the binding sites of small molecules and peptide inhibitors. There are a number of advantages of EM over the more traditional X-ray crystallographic approach, such as resolving different conformational states and permitting the dynamics of a system to be better resolved when not constrained by a crystal lattice...
June 1, 2017: Acta Crystallographica. Section D, Structural Biology
https://www.readbyqxmd.com/read/28579436/intranasal-vaccination-with-an-adjuvanted-polyphosphazenes-nanoparticle-based-vaccine-formulation-stimulates-protective-immune-responses-in-mice
#6
Kai Schulze, Thomas Ebensen, Lorne A Babiuk, Volker Gerdts, Carlos A Guzman
The most promising strategy to sustainably prevent infectious diseases is vaccination. However, emerging as well as re-emerging diseases still constitute a considerable threat. Furthermore, lack of compliance and logistic constrains often result in the failure of vaccination campaigns. To overcome these hurdles, novel vaccination strategies need to be developed, which fulfill maximal safety requirements, show maximal efficiency and are easy to administer. Mucosal vaccines constitute promising non-invasive approaches able to match these demands...
June 1, 2017: Nanomedicine: Nanotechnology, Biology, and Medicine
https://www.readbyqxmd.com/read/28570824/protein-epitope-mimetics-from-new-antibiotics-to-supramolecular-synthetic-vaccines
#7
Katja Zerbe, Kerstin Moehle, John A Robinson
Protein epitope mimetics provide powerful tools to study biomolecular recognition in many areas of chemical biology. They may also provide access to new biologically active molecules and potentially to new classes of drug and vaccine candidates. Here we highlight approaches for the design of folded, structurally defined epitope mimetics, by incorporating backbone and side chains of hot residues onto a stable constrained scaffold. Using robust synthetic methods, the structural, biological, and physical properties of epitope mimetics can be optimized, by variation of both side chain and backbone chemistry...
June 1, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28561588/protein-domain-mimics-as-modulators-of-protein-protein-interactions
#8
Nicholas Sawyer, Andrew M Watkins, Paramjit S Arora
Protein-protein interactions (PPIs) are ubiquitous in biological systems and often misregulated in disease. As such, specific PPI modulators are desirable to unravel complex PPI pathways and expand the number of druggable targets available for therapeutic intervention. However, the large size and relative flatness of PPI interfaces make them challenging molecular targets. This Account describes our systematic approach using secondary and tertiary protein domain mimics (PDMs) to specifically modulate PPIs. Our strategy focuses on mimicry of regular secondary and tertiary structure elements from one of the PPI partners to inspire rational PDM design...
May 31, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28561582/interplay-of-stereochemistry-conformational-rigidity-and-ease-of-synthesis-for-13-membered-cyclic-peptidomimetics-containing-apc-residues
#9
Dongyue Xin, Andrew Jeffries, Kevin Burgess
As part of a program to design small molecules that bind proteins, we require cyclic peptides (or peptidomimetics) that are severely constrained such that they adopt one predominant conformation in solution. This paper describes syntheses of the 13-membered cyclic tetrapeptides 1 containing aminopyrrolidine carboxyl (APC) residues. A linear precursor was prepared and used to determine optimal conditions for cyclization of that substrate. A special linker was prepared to enable cyclization of similar linear peptidomimetics on a solid phase, and the solution-phase cyclization conditions were shown to be appropriate for this too...
May 31, 2017: ACS Combinatorial Science
https://www.readbyqxmd.com/read/28528775/structural-basis-for-apelin-control-of-the-human-apelin-receptor
#10
Yingli Ma, Yang Yue, Yanbin Ma, Qing Zhang, Qingtong Zhou, Yunpeng Song, Yuqing Shen, Xun Li, Xiaochuan Ma, Chao Li, Michael A Hanson, Gye Won Han, E Allen Sickmier, Gayathri Swaminath, Suwen Zhao, Raymond C Stevens, Liaoyuan A Hu, Wenge Zhong, Mingqiang Zhang, Fei Xu
Apelin receptor (APJR) is a key regulator of human cardiovascular function and is activated by two different endogenous peptide ligands, apelin and Elabela, each with different isoforms diversified by length and amino acid sequence. Here we report the 2.6-Å resolution crystal structure of human APJR in complex with a designed 17-amino-acid apelin mimetic peptide agonist. The structure reveals that the peptide agonist adopts a lactam constrained curved two-site ligand binding mode. Combined with mutation analysis and molecular dynamics simulations with apelin-13 binding to the wild-type APJR, this structure provides a mechanistic understanding of apelin recognition and binding specificity...
June 6, 2017: Structure
https://www.readbyqxmd.com/read/28524918/urotensin-ii-peptidomimetic-incorporating-a-non-reducible-1-5-triazole-disulfide-bond-reveals-a-pseudo-irreversible-covalent-binding-mechanism-to-the-urotensin-g-protein-coupled-receptor
#11
Salvatore Pacifico, Aidan Kerckhoffs, Andrew J Fallow, Rachel E Foreman, Remo Guerrini, John McDonald, David G Lambert, Andrew G Jamieson
The urotensin-II receptor (UTR) is a class A GPCR that predominantly binds to the pleiotropic cyclic peptide urotensin-II (U-II). U-II is constrained by a disulfide bridge that induces a β-turn structure and binds pseudo-irreversibly to UTR and is believed to result in a structural rearrangement of the receptor. However, it is not well understood how U-II binds pseudo-irreversibly and the nature of the reorganization of the receptor that results in G-protein activation. Here we describe a series of U-II peptidomimetics incorporating a non-reducible disulfide bond structural surrogate to investigate the feasibility that native U-II binds to the G protein-coupled receptor through disulfide bond shuffling as a mechanism of covalent interaction...
May 31, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28497389/elucidating-and-engineering-thiopeptide-biosynthesis
#12
REVIEW
Philip R Bennallack, Joel S Griffitts
Initially discovered in the mid-twentieth century, thiopeptides constitute a diverse family of bacterially produced natural products exhibiting a remarkable array of biological properties. Only in the last several years have the details of thiopeptide biosynthesis been uncovered by a combination of genomic, genetic, and biochemical approaches. Thiopeptides are now known to be ribosomally synthesized and subsequently densely modified to carry azol(in)es, dehydro amino acids, and various other pathway-specific decorations...
June 2017: World Journal of Microbiology & Biotechnology
https://www.readbyqxmd.com/read/28486273/zebularine-treatment-induces-mage-a11-expression-and-improves-ctl-cytotoxicity-using-a-novel-identified-hla-a2-restricted-mage-a11-peptide
#13
Jiandong Zhang, Meixiang Sang, Lina Gu, Fei Liu, Weijing Li, Danjing Yin, Yunyan Wu, Shina Liu, Weina Huang, Baoen Shan
Melanoma-associated antigen-A11 (MAGE-A11) is frequently expressed in breast cancer and is associated with poor prognosis. Therefore, MAGE-A11 is a potential immunotherapy target in breast cancer. MAGE-A11 expression, however, is downregulated in many patients, thus constraining the application of immunotherapy. The induction of MAGE-A11 expression is crucial for the recognition and killing of breast cancer cells by cytotoxic T lymphocytes (CTL). In this study, a series of HLA-A2-restricted candidate MAGE-A11 peptides were predicted, synthesized, and tested...
July 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/28454062/self-assembled-dehydropeptide-nano-carriers-for-delivery-of-ornidazole-and-curcumin
#14
Smriti Rekha Deka, Santosh Yadav, Dheeresh Kumar, Sumit Garg, Manohar Mahato, Ashwani Kumar Sharma
In the recent studies, it has been demonstrated that incorporation of unnatural amino acid, α,β-dehydrophenylalanine, in small peptides results in stable self-assembled nanostructures with different sizes and shapes. Here, we have replaced the natural amino acid, phenylalanine, from our earlier reported work on self-assembled peptide, Boc-Pro-Phe-Gly-OMe, with a constrained dehydro amino acid, α,β-dehydrophenylalanine, to study its influence on self-assembled nanostructures. Dehydrotripeptide, Boc-Pro-ΔPhe-Gly-OMe, self-assembled into nanostructures in aqueous solutions and formed hydrophobic matrix with improved encapsulation efficiency of hydrophobic molecules...
April 20, 2017: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/28451100/non-covalent-s%C3%A2-%C3%A2-%C3%A2-o-interactions-control-conformation-in-a-scaffold-that-disrupts-islet-amyloid-polypeptide-fibrillation
#15
Hayden Peacock, Jinghui Luo, Tohru Yamashita, James Luccarelli, Sam Thompson, Andrew D Hamilton
Conformationally-constrained molecules that selectively recognise the surfaces of proteins have the potential to direct the path of protein folding. Such molecules are of therapeutic interest because the misfolding of proteins, especially that which results in fibrillation and aggregation, is strongly correlated with numerous diseases. Here we report the novel use of S···O interactions as a conformational control element in a new class of non-peptidic scaffold that mimics key elements of protein surfaces...
October 1, 2016: Chemical Science
https://www.readbyqxmd.com/read/28445507/various-mutations-compensate-for-a-deleterious-lacz%C3%AE-insert-in-the-replication-enhancer-of-m13-bacteriophage
#16
Emily M Zygiel, Karen A Noren, Marta A Adamkiewicz, Richard J Aprile, Heather K Bowditch, Christine L Carroll, Maria Abigail S Cerezo, Adelle M Dagher, Courtney R Hebert, Lauren E Hebert, Gloria M Mahame, Stephanie C Milne, Kelly M Silvestri, Sara E Sutherland, Alexandria M Sylvia, Caitlyn N Taveira, David J VanValkenburgh, Christopher J Noren, Marilena Fitzsimons Hall
M13 and other members of the Ff class of filamentous bacteriophages have been extensively employed in myriad applications. The Ph.D. series of phage-displayed peptide libraries were constructed from the M13-based vector M13KE. As a direct descendent of M13mp19, M13KE contains the lacZα insert in the intergenic region between genes IV and II, where it interrupts the replication enhancer of the (+) strand origin. Phage carrying this 816-nucleotide insert are viable, but propagate in E. coli at a reduced rate compared to wild-type M13 phage, presumably due to a replication defect caused by the insert...
2017: PloS One
https://www.readbyqxmd.com/read/28429026/n-difluoromethyl-triazole-as-a-constrained-scaffold-in-peptidomimetics
#17
M Mamone, R S B Gonçalves, F Blanchard, G Bernadat, S Ongeri, T Milcent, B Crousse
The N-difluoromethyl triazolo-β-aza-ε-amino acid present in the core of peptides led to constrained conformations due to CH-F and NH-F interactions. Pseudotetrapeptides were obtained in excellent yields directly by click chemistry between azidodifluoroacetamides and alkynes, both linked to an amino acid. This work demonstrates that the N-difluoromethyltriazole scaffold can induce extended structures to β-strand mimics.
April 21, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28398045/conformational-effects-through-hydrogen-bonding-in-a-constrained-%C3%AE-peptide-template-from-intraresidue-seven-membered-rings-to-a-gel-forming-sheet-structure
#18
Hawraà Awada, Claire M Grison, Florence Charnay-Pouget, Jean-Pierre Baltaze, François Brisset, Régis Guillot, Sylvie Robin, Ali Hachem, Nada Jaber, Daoud Naoufal, Ogaritte Yazbeck, David J Aitken
A series of three short oligomers (di-, tri-, and tetramers) of cis-2-(aminomethyl)cyclobutane carboxylic acid, a γ-amino acid featuring a cyclobutane ring constraint, were prepared, and their conformational behavior was examined spectroscopically and by molecular modeling. In dilute solutions, these peptides showed a number of low-energy conformers, including ribbonlike structures pleated around a rarely observed series of intramolecular seven-membered hydrogen bonds. In more concentrated solutions, these interactions defer to an organized supramolecular assembly, leading to thermoreversible organogel formation notably for the tripeptide, which produced fibrillar xerogels...
May 5, 2017: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28363796/structure-constrained-endomorphin-analogs-display-differential-antinociceptive-mechanisms-in-mice-after-spinal-administration
#19
Yuan Wang, Jingjing Zhou, Xin Liu, Long Zhao, Zhaojuan Wang, Xianghui Zhang, Kezhou Wang, Linqing Wang, Rui Wang
We previously reported a series of novel endomorphin analogs with unnatural amino acid modifications. These analogs display good binding affinity and functional activity toward the μ opioid receptor (MOP). In the present study, we further investigated the spinal antinociceptive activity of these compounds. The analogs were potent in several nociceptive models. Opioid antagonists and antibodies against several endogenous opioid peptides were used to determine the mechanisms of action of these peptides. Intrathecal pretreatment with naloxone and β-funaltrexamine (β-FNA) effectively inhibited analog-induced analgesia, demonstrating that activity of the analogs is regulated primarily through MOP...
May 2017: Peptides
https://www.readbyqxmd.com/read/28326635/structure-enabled-discovery-of-a-stapled-peptide-inhibitor-to-target-the-oncogenic-transcriptional-repressor-tle1
#20
Sally McGrath, Marcello Tortorici, Ludovic Drouin, Savade Solanki, Lewis Vidler, Isaac Westwood, Peter Gimeson, Rob vanMontfort, Swen Hoelder
TLE1 is an oncogenic transcriptional co-repressor that exerts its repressive effects through binding of transcription factors. Inhibition of this protein-protein interaction represents a putative cancer target but no small molecule inhibitors have been published for this challenging interface. In this manuscript, we report the structure enabled design and synthesis of a constrained peptide inhibitor of TLE1. Our design featured introduction of a four carbon atom linker into the peptide epitope found in many TLE1 binding partners...
March 22, 2017: Chemistry: a European Journal
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