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Alpha helix mimetic

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https://www.readbyqxmd.com/read/27910980/carbonylation-as-a-novel-method-for-the-assembly-of-pyrazine-based-oligoamide-alpha-helix-mimetics
#1
Seger Van Mileghem, Brecht Egle, Philippe Gilles, Cedrick Veryser, Luc Van Meervelt, Wim M De Borggraeve
The design and synthesis of oligoamide α-helix peptidomimetics is reported. The oligoamide type systems are prepared in a modular fashion by coupling the monomers using palladium-catalyzed carbonylation chemistry. This enabled us to use substrates with a low nucleophilicity, leading to previously unreported pyrazine based oligoamide α-helix mimetics. The proof of principle is given by synthesizing a small set of compounds. Various end-capping groups were introduced and also a mixed multimer was successfully prepared...
December 2, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27434090/modulating-transmembrane-%C3%AE-helix-interactions-through-ph-sensitive-boundary-residues
#2
Derek P Ng, Charles M Deber
Changes in pH can alter the structure and activity of proteins and may be used by the cell to control molecular function. This coupling can also be used in non-native applications through the design of pH-sensitive biomolecules. For example, the pH (low) insertion peptide (pHLIP) can spontaneously insert into a lipid bilayer when the pH decreases. We have previously shown that the α-helicity and helix-helix interactions of the TM2 α-helix of the proteolipid protein (PLP) are sensitive to the local hydrophobicity at its C-terminus...
August 9, 2016: Biochemistry
https://www.readbyqxmd.com/read/27050713/discovery-and-structure-activity-relationships-of-the-neoseptins-a-new-class-of-toll-like-receptor-4-tlr4-agonists
#3
Matthew D Morin, Ying Wang, Brian T Jones, Lijing Su, Murali M R P Surakattula, Michael Berger, Hua Huang, Elliot K Beutler, Hong Zhang, Bruce Beutler, Dale L Boger
Herein, we report studies leading to the discovery of the neoseptins and a comprehensive examination of the structure-activity relationships (SARs) of this new class of small-molecule mouse Toll-like receptor 4 (mTLR4) agonists. The compounds in this class, which emerged from screening an α-helix mimetic library, stimulate the immune response, act by a well-defined mechanism (mouse TLR4 agonist), are easy to produce and structurally manipulate, exhibit exquisite SARs, are nontoxic, and elicit improved and qualitatively different responses compared to lipopolysaccharide, even though they share the same receptor...
May 26, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/26690307/probing-protein-surfaces-qsar-analysis-with-helix-mimetics
#4
Valeria Azzarito, Philip Rowell, Anna Barnard, Thomas A Edwards, Andrew Macdonald, Stuart L Warriner, Andrew J Wilson
α-Helix-mediated protein-protein interactions (PPIs) are important targets for small-molecule inhibition; however, generic approaches to inhibitor design are in their infancy and would benefit from QSAR analyses to rationalise the noncovalent basis of molecular recognition by designed ligands. Using a helix mimetic based on an oligoamide scaffold, we have exploited the power of a modular synthesis to access compounds that can readily be used to understand the noncovalent determinants of hDM2 recognition by this series of cell-active p53/hDM2 inhibitors...
April 15, 2016: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/26189498/a-thiol-ene-coupling-approach-to-native-peptide-stapling-and-macrocyclization
#5
Yuanxiang Wang, Danny Hung-Chieh Chou
We report the discovery of a peptide stapling and macrocyclization method using thiol-ene reactions between two cysteine residues and an α,ω-diene in high yields. This new approach enabled us to selectively modify cysteine residues in native, unprotected peptides with a variety of stapling modifications for helix stabilization or general macrocyclization. We synthesized stapled Axin mimetic analogues and demonstrated increased alpha helicity upon peptide stapling. We then synthesized stapled p53 mimetic analogues using pure hydrocarbon linkers and demonstrated their abilities to block the p53-MDM2 interaction and selectively kill p53 wild-type colorectal carcinoma HCT-116 cells but not p53 null cells...
September 7, 2015: Angewandte Chemie
https://www.readbyqxmd.com/read/26177543/the-human-autoantibody-response-to-apolipoprotein-a-i-is-focused-on-the-c-terminal-helix-a-new-rationale-for-diagnosis-and-treatment-of-cardiovascular-disease
#6
Sabrina Pagano, Hubert Gaertner, Fabrice Cerini, Tiphaine Mannic, Nathalie Satta, Priscila Camillo Teixeira, Paul Cutler, François Mach, Nicolas Vuilleumier, Oliver Hartley
BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death worldwide and new approaches for both diagnosis and treatment are required. Autoantibodies directed against apolipoprotein A-I (ApoA-I) represent promising biomarkers for use in risk stratification of CVD and may also play a direct role in pathogenesis. METHODOLOGY: To characterize the anti-ApoA-I autoantibody response, we measured the immunoreactivity to engineered peptides corresponding to the different alpha-helical regions of ApoA-I, using plasma from acute chest pain cohort patients known to be positive for anti-ApoA-I autoantibodies...
2015: PloS One
https://www.readbyqxmd.com/read/25986737/biochemical-characterization-of-a-heterotrimeric-g-i-protein-activator-peptide-designed-from-the-junction-between-the-intracellular-third-loop-and-sixth-transmembrane-helix-in-the-m4-muscarinic-acetylcholine-receptor
#7
Shin-ichi Terawaki, Rina Matsubayashi, Kanako Hara, Tatsuki Onozuka, Toshiyuki Kohno, Kaori Wakamatsu
Muscarinic acetylcholine receptors (mAChRs) are G-protein coupled receptors (GPCRs) that are activated by acetylcholine released from parasympathetic nerves. The mAChR family comprises 5 subtypes, m1-m5, each of which has a different coupling selectivity for heterotrimeric GTP-binding proteins (G-proteins). m4 mAChR specifically activates the Gi/o family by enhancing the guanine nucleotide exchange factor (GEF) reaction with the Gα subunit through an interaction that occurs via intracellular segments. Here, we report that the m4 mAChR mimetic peptide m4i3c(14)Gly, comprising 14 residues in the junction between the intracellular third loop (i3c) and transmembrane helix VI (TM-VI) extended with a C-terminal glycine residue, presents GEF activity toward the Gi1 α subunit (Gαi1)...
July 17, 2015: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/25934391/allosteric-activation-of-a-g-protein-coupled-receptor-with-cell-penetrating-receptor-mimetics
#8
Ping Zhang, Andrew J Leger, James D Baleja, Rajashree Rana, Tiffany Corlin, Nga Nguyen, Georgios Koukos, Andrew Bohm, Lidija Covic, Athan Kuliopulos
G protein-coupled receptors (GPCRs) are remarkably versatile signaling systems that are activated by a large number of different agonists on the outside of the cell. However, the inside surface of the receptors that couple to G proteins has not yet been effectively modulated for activity or treatment of diseases. Pepducins are cell-penetrating lipopeptides that have enabled chemical and physical access to the intracellular face of GPCRs. The structure of a third intracellular (i3) loop agonist, pepducin, based on protease-activated receptor-1 (PAR1) was solved by NMR and found to closely resemble the i3 loop structure predicted for the intact receptor in the on-state...
June 19, 2015: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/25825775/targeting-diverse-protein-protein-interaction-interfaces-with-%C3%AE-%C3%AE-peptides-derived-from-the-z-domain-scaffold
#9
James W Checco, Dale F Kreitler, Nicole C Thomas, David G Belair, Nicholas J Rettko, William L Murphy, Katrina T Forest, Samuel H Gellman
Peptide-based agents derived from well-defined scaffolds offer an alternative to antibodies for selective and high-affinity recognition of large and topologically complex protein surfaces. Here, we describe a strategy for designing oligomers containing both α- and β-amino acid residues ("α/β-peptides") that mimic several peptides derived from the three-helix bundle "Z-domain" scaffold. We show that α/β-peptides derived from a Z-domain peptide targeting vascular endothelial growth factor (VEGF) can structurally and functionally mimic the binding surface of the parent peptide while exhibiting significantly decreased susceptibility to proteolysis...
April 14, 2015: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/24972345/rational-design-of-topographical-helix-mimics-as-potent-inhibitors-of-protein-protein-interactions
#10
Brooke Bullock Lao, Kevin Drew, Danielle A Guarracino, Thomas F Brewer, Daniel W Heindel, Richard Bonneau, Paramjit S Arora
Protein-protein interactions encompass large surface areas, but often a handful of key residues dominate the binding energy landscape. Rationally designed small molecule scaffolds that reproduce the relative positioning and disposition of important binding residues, termed "hotspot residues", have been shown to successfully inhibit specific protein complexes. Although this strategy has led to development of novel synthetic inhibitors of protein complexes, often direct mimicry of natural amino acid residues does not lead to potent inhibitors...
June 4, 2014: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/24821806/in-vivo-modulation-of-hypoxia-inducible-signaling-by-topographical-helix-mimetics
#11
Brooke Bullock Lao, Ivan Grishagin, Hanah Mesallati, Thomas F Brewer, Bogdan Z Olenyuk, Paramjit S Arora
Development of small-molecule inhibitors of protein-protein interactions is a fundamental challenge at the interface of chemistry and cancer biology. Successful methods for design of protein-protein interaction inhibitors include computational and experimental high-throughput and fragment-based screening strategies to locate small-molecule fragments that bind protein surfaces. An alternative rational design approach seeks to mimic the orientation and disposition of critical binding residues at protein interfaces...
May 27, 2014: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/24782431/small-molecule-proteomimetic-inhibitors-of-the-hif-1%C3%AE-p300-protein-protein-interaction
#12
George M Burslem, Hannah F Kyle, Alexander L Breeze, Thomas A Edwards, Adam Nelson, Stuart L Warriner, Andrew J Wilson
The therapeutically relevant hypoxia inducible factor HIF-1α-p300 protein-protein interaction can be orthosterically inhibited with α-helix mimetics based on an oligoamide scaffold that recapitulates essential features of the C-terminal helix of the HIF-1α C-TAD (C-terminal transactivation domain). Preliminary SAR studies demonstrated the important role of side-chain size and hydrophobicity/hydrophilicity in determining potency. These small molecules represent the first biophysically characterised HIF-1α-p300 PPI inhibitors and the first examples of small-molecule aromatic oligoamide helix mimetics to be shown to have a selective binding profile...
May 26, 2014: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/24297451/molecular-dynamics-simulation-of-human-serum-paraoxonase-1-in-dppc-bilayer-reveals-a-critical-role-of-transmembrane-helix-h1-for-hdl-association
#13
Mahesh Chandra Patra, Surya Narayan Rath, Sukanta Kumar Pradhan, Jitendra Maharana, Sachinandan De
Serum paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-bound mammalian enzyme exhibiting antiatherosclerotic activity. Despite years of research, an accurate model for the binding interaction between PON1 and HDL has not been established. However, it is reported that anchoring of PON1 to HDL is mainly governed by an N-terminal alpha helix H1 and another short helix H2. Here, we studied the molecular association of full-length human PON1 (huPON1) with a HDL-mimetic dipalmitoylphosphatidylcholine (DPPC) bilayer using homology modeling and molecular dynamics simulations...
January 2014: European Biophysics Journal: EBJ
https://www.readbyqxmd.com/read/24048733/antidicer-rnase-activity-of-monocyte-chemotactic-protein-induced-protein-1-is-critical-for-inducing-angiogenesis
#14
Arpita Roy, Miaojun Zhang, Yasser Saad, Pappachan E Kolattukudy
Inflammatory angiogenesis involves the induction of a novel gene ZC3H12A encoding monocyte chemoattractant protein-1 (MCP-1)-induced protein-1 (MCPIP1) that has deubiquitinase and antidicer RNAse activities. If and how these enzymatic activities of MCPIP1 mediate the biological functions of MCPIP1 are unknown. Present studies with human umbilical vein endothelial cells suggest that MCPIP-induced angiogenesis is mediated via hypoxia-inducible factor (HIF-1α), vascular endothelial growth factor (VEGF), and silent information regulator (SIRT-1) induction that results in the inhibition of angiogenesis inhibitor thrombospondin-1...
November 15, 2013: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/23958427/cobalt-stimulates-hif-1-dependent-but-inhibits-hif-2-dependent-gene-expression-in-liver-cancer-cells
#15
Christina Befani, Ilias Mylonis, Ioanna-Maria Gkotinakou, Panagiotis Georgoulias, Cheng-Jun Hu, George Simos, Panagiotis Liakos
Hypoxia-inducible factors (HIFs) are transcriptional regulators that mediate the cellular response to low oxygen. Although HIF-1 is usually considered as the principal mediator of hypoxic adaptation, several tissues and different cell types express both HIF-1 and HIF-2 isoforms under hypoxia or when treated with hypoxia mimetic chemicals such as cobalt. However, the similarities or differences between HIF-1 and HIF-2, in terms of their tissue- and inducer-specific activation and function, are not adequately characterized...
November 2013: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/23768251/computational-analysis-of-protein-protein-interfaces-involving-an-alpha-helix-insights-for-terphenyl-like-molecules-binding
#16
Adriana Isvoran, Dana Craciun, Virginie Martiny, Olivier Sperandio, Maria A Miteva
BACKGROUND: Protein-Protein Interactions (PPIs) are key for many cellular processes. The characterization of PPI interfaces and the prediction of putative ligand binding sites and hot spot residues are essential to design efficient small-molecule modulators of PPI. Terphenyl and its derivatives are small organic molecules known to mimic one face of protein-binding alpha-helical peptides. In this work we focus on several PPIs mediated by alpha-helical peptides. METHOD: We performed computational sequence- and structure-based analyses in order to evaluate several key physicochemical and surface properties of proteins known to interact with alpha-helical peptides and/or terphenyl and its derivatives...
June 14, 2013: BMC Pharmacology & Toxicology
https://www.readbyqxmd.com/read/23746270/targeting-the-bh3-domain-of-bcl-2-family-proteins-a-brief-history-from-natural-products-to-foldamers-as-promising-cancer-therapeutic-avenues
#17
REVIEW
M De Giorgi, A S Voisin-Chiret, S Rault
For many years the spotlight in drug discovery has been on a relatively small number of validated therapeutic target classes, such as G-protein coupled receptors and enzymes such as protein kinases, with well characterized enzymatic and cellular activities. However, with recent progress in genomics and proteomics, protein-protein interactions (PPIs) provide new way of finding novel bioactive molecules acting on their interfaces. This review addresses the current case studies and state of the art in the development of small chemical modulators controlling interactions of proteins that have pathological implications in various human diseases and in particular in cancer...
2013: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/22943412/bafilomycin-a1-activates-hif-dependent-signalling-in-human-colon-cancer-cells-via-mitochondrial-uncoupling
#18
Alexander V Zhdanov, Ruslan I Dmitriev, Dmitri B Papkovsky
Mitochondrial uncoupling is implicated in many patho(physiological) states. Using confocal live cell imaging and an optical O2 sensing technique, we show that moderate uncoupling of the mitochondria with plecomacrolide Baf (bafilomycin A1) causes partial depolarization of the mitochondria and deep sustained deoxygenation of human colon cancer HCT116 cells subjected to 6% atmospheric O2. A decrease in iO2 (intracellular O2) to 0-10 μM, induced by Baf, is sufficient for stabilization of HIFs (hypoxia inducible factors) HIF-1α and HIF-2α, coupled with an increased expression of target genes including GLUT1 (glucose transporter 1), HIF PHD2 (prolyl hydroxylase domain 2) and CAIX (carbonic anhydrase IX)...
December 2012: Bioscience Reports
https://www.readbyqxmd.com/read/22664089/targeting-quorum-sensing-and-competence-stimulation-for-antimicrobial-chemotherapy
#19
Nicholas E Shepherd, Rosemary S Harrison, David P Fairlie
Bacterial resistance to antibiotics is now a serious problem, with traditional classes of antibiotics having gradually become ineffective. New drugs are therefore needed to target and inhibit novel pathways that affect the growth of bacteria. An important feature in the survival of bacteria is that they coordinate their efforts together as a colony via secreted auto-inducing molecules. Competence stimulating peptides (CSPs) are among the quorum sensing pheromones involved in this coordination. These peptides activate a two-component system in gram-negative bacteria, binding to and activating a histidine kinase receptor called ComD, which phosphorylates a response regulator called ComE, leading to gene expression and induction of competence...
October 2012: Current Drug Targets
https://www.readbyqxmd.com/read/22277691/increased-activation-of-the-hypoxia-inducible-factor-pathway-in-varicose-veins
#20
Chung S Lim, Serafim Kiriakidis, Ewa M Paleolog, Alun H Davies
BACKGROUND: Venous hypoxia has been postulated to contribute to varicose vein (VV) formation. Direct measurements of vein wall oxygen tension have previously demonstrated that the average minimum oxygen tensions were significantly lower in VVs compared with non-varicose veins (NVVs). Hypoxia-inducible factors (HIFs) are nuclear transcriptional factors that regulate the expression of several genes of oxygen homeostasis. This study aimed to investigate if hypoxia was associated with VVs by assessing the expression of HIF-1α, HIF-2α, HIF target genes, and upstream HIF regulatory enzymes in VVs and NVVs, and their regulation by hypoxia...
May 2012: Journal of Vascular Surgery
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