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Constrained peptide

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
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...
December 5, 2016: Angewandte Chemie
Keiichi Masuya
No abstract text is available yet for this article.
2016: Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica
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.
November 23, 2016: Organic & Biomolecular Chemistry
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...
November 9, 2016: Bioorganic & Medicinal Chemistry
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
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
Christelle Ganneau, Catherine Simenel, Emeline Emptas, Tiphanie Courtiol, Yves-Marie Coïc, Cécile Artaud, Edith Dériaud, Frédéric Bonhomme, Muriel Delepierre, Claude Leclerc, Richard Lo-Man, Sylvie Bay
Herein, we report a new process that enables the gram-scale production of a fully synthetic anti-cancer vaccine for human use. This therapeutic vaccine candidate, named MAG-Tn3, is a high-molecular-weight tetrameric glycopeptide encompassing carbohydrate tumor-associated Tn antigen clusters and peptidic CD4(+) T-cell epitopes. The synthetic process involves (i) the stepwise solid-phase assembly of protected amino acids, including the high value-added Tn building blocks with only 1.5 equivalents, (ii) a single isolated intermediate, and (iii) the simultaneous deprotection of 36 hindered protective groups...
November 4, 2016: Organic & Biomolecular Chemistry
Oleg M Michurin, Sergii Afonin, Marina Berditsch, Constantin G Daniliuc, Anne S Ulrich, Igor V Komarov, Dmytro S Radchenko
Conformationally constrained non-racemizing trifluoromethyl-substituted lysine isosteres [(E)- and (Z)-TCBLys] with charged side chains are presented as a new type of (19) F-NMR labels for peptide studies. Design of the labels, their synthesis, incorporation into peptides and experimental demonstration of their application for solid state NMR studies of membrane-active peptides are described. A series of fluorine-labeled analogues of the helical amphipathic antimicrobial peptide PGLa(Nle) was obtained, in which different lysine residues in the original peptide sequence were replaced, one at a time, by either (E)- or (Z)-TCBLys...
November 14, 2016: Angewandte Chemie
Kenneth E Schwieter, Jeffrey N Johnston
Peptide synthesis is a truly interdisciplinary tool, familiar to a broad group of scientists who do not otherwise overlap scientifically. For this reason, some may perceive even complex peptide synthesis to be a "solved problem", while others might argue that immense opportunity remains untapped or simply inaccessible. At the extreme of complexity, what might a concise assessment of the state-of-the-art in peptide synthesis look like? As one of the most practiced forms of synthetic chemistry by chemists and non-chemists alike, what restrictions remain that constrain access to chemical space? Using popular terminology, what forms of peptide synthesis are appropriately termed "on-demand"? The purpose of this Perspective is to appraise synthetic access to complex peptides, particularly those containing unnatural α-amino amides...
October 14, 2016: Journal of the American Chemical Society
Carmen Burtea, Sophie Laurent, Tuba Sanli, Deborah Fanfone, Aude Devalckeneer, Sébastien Sauvage, Marie-Claire Beckers, Sandrine Rorive, Isabelle Salmon, Luce Vander Elst, Bernard R Lauwerys, Robert N Muller
BACKGROUND: Interleukin-7 receptor alpha (IL-7Rα) represents a biomarker with potential applications in rheumatoid arthritis (RA) diagnosis and therapy. We have therefore searched by phage display potential IL-7Rα specific peptides with the primary goal being to develop in vivo molecular imaging tools. METHODS: IL-7Rα-targeted peptides were searched within a disulfide-constrained combinatorial phage displayed library of random linear heptapeptides. The apparent dissociation constant (Kd) and half maximal inhibition constant (IC50) were estimated for phage clones and synthesized peptides by ELISA...
October 12, 2016: Arthritis Research & Therapy
Kelly L Keeling, Okki Cho, Denis B Scanlon, Grant W Booker, Andrew D Abell, Kate L Wegener
Constrained α-helical peptides are showing potential as biological probes and therapeutic agents that target protein-protein interactions. However, the factors that determine the optimal constraint locations are still largely unknown. Using the β-integrin/talin protein interaction as a model system, we examine the effect of constraint location on helical conformation, as well as binding affinity, using circular dichroism and NMR spectroscopy. Stapling increased the overall helical content of each integrin-based peptide tested...
October 18, 2016: Organic & Biomolecular Chemistry
Yuksel Batir, Thaddeus A Bargiello, Terry L Dowd
In this article we present (1)H and (13)C chemical shift assignments, secondary structural propensity data and normalized temperature coefficient data for N-terminal peptides of Connexin 26 (Cx26), Cx26G12R and Cx32G12R mutants seen in syndromic deafness and Charcot Marie Tooth Disease respectively, published in "Structural Studies of N-Terminal Mutants of Connexin 26 and Connexin 32 Using 1H NMR Spectroscopy" (Y. Batir, T.A. Bargiello, T.L. Dowd, 2016) [1]. The mutation G12R affects the structure of both Cx26 and Cx32 peptides differently...
December 2016: Data in Brief
Nina Bionda, Rudi Fasan
Many biologically active peptides found in nature exhibit a bicyclic structure wherein a head-to-tail cyclic backbone is further constrained by an intramolecular linkage connecting two side chains of the peptide. Accordingly, methods to access macrocyclic peptides sharing this overall topology could be of significant value toward the discovery of new functional entities and bioactive compounds. With this goal in mind, we recently developed a strategy for enabling the biosynthesis of thioether-bridged bicyclic peptides in living bacterial cells...
2017: Methods in Molecular Biology
Alysha G Elliott, Bastian Franke, David A Armstrong, David J Craik, Joshua S Mylne, K Johan Rosengren
We recently isolated and described the evolutionary origin of a diverse class of small single-disulfide bonded peptides derived from Preproalbumin with SFTI-1 (PawS1) proteins in the seeds of flowering plants (Asteraceae). The founding member of the PawS derived peptide (PDP) family is the potent trypsin inhibitor SFTI-1 (sunflower trypsin inhibitor-1) from Helianthus annuus, the common sunflower. Here we provide additional structures and describe the structural diversity of this new class of small peptides, derived from solution NMR studies, in detail...
October 1, 2016: Amino Acids
Olivier Van der Poorten, Astrid Knuhtsen, Daniel Sejer Pedersen, Steven Ballet, Dirk Tourwé
Constraining the conformation of flexible peptides is a proven strategy to increase potency, selectivity and metabolic stability. The focus has mostly been on constraining the backbone dihedral angles; however, the correct orientation of the amino acid side chains (Χ-space) which constitute the peptide pharmacophore is equally important. Control of Χ-space utilizes conformationally constrained amino acids which favor, disfavor or exclude the gauche (‒), the gauche (+) or the trans conformation. In this review we focus on cyclic aromatic amino acids in which the side chain is connected to the peptide backbone to provide control of Χ1- and Χ2-space...
October 3, 2016: Journal of Medicinal Chemistry
Gaurav Bhardwaj, Vikram Khipple Mulligan, Christopher D Bahl, Jason M Gilmore, Peta J Harvey, Olivier Cheneval, Garry W Buchko, Surya V S R K Pulavarti, Quentin Kaas, Alexander Eletsky, Po-Ssu Huang, William A Johnsen, Per Jr Greisen, Gabriel J Rocklin, Yifan Song, Thomas W Linsky, Andrew Watkins, Stephen A Rettie, Xianzhong Xu, Lauren P Carter, Richard Bonneau, James M Olson, Evangelos Coutsias, Colin E Correnti, Thomas Szyperski, David J Craik, David Baker
Naturally occurring, pharmacologically active peptides constrained with covalent crosslinks generally have shapes that have evolved to fit precisely into binding pockets on their targets. Such peptides can have excellent pharmaceutical properties, combining the stability and tissue penetration of small-molecule drugs with the specificity of much larger protein therapeutics. The ability to design constrained peptides with precisely specified tertiary structures would enable the design of shape-complementary inhibitors of arbitrary targets...
September 14, 2016: Nature
Eva Schütznerová, Pedro Verdía, Viktor Krchňák
3,4,4a,5-Tetrahydrobenzo[e]pyrazino[2,1-c][1,2,4]thiadiazin-1(2H)-one 6,6-dioxides, molecular scaffolds with 3D architecture, were synthesized on solid supports via tandem N-acyl iminium ion cyclization followed by nucleophilic addition. The modular synthesis proceeded under mild conditions using commercially available building blocks and provided crude products with respectable purity. The synthesized compounds are applicable as fused nitrogenous heterocyclic compounds in drug discovery and as constrained peptidomimetics incorporated into a peptide backbone...
October 10, 2016: ACS Combinatorial Science
Olivier M F Martin, Loïc Etheve, Guillaume Launay, Juliette Martin
Terminal residues of protein chains are charged and more flexible than other residues since they are constrained only on one side. Do they play a particular role in protein-protein and protein-DNA interfaces? To answer this question, we considered large sets of non-redundant protein-protein and protein-DNA complexes and analyzed the status of terminal residues and their involvement in interfaces. In protein-protein complexes, we found that more than half of terminal residues (62%) are either modified by attachment of a tag peptide (10%) or have missing coordinates in the analyzed structures (52%)...
2016: PloS One
Eivind A B Undheim, Ronald A Jenner, Glenn F King
INTRODUCTION: Centipedes are one of the oldest and most successful lineages of venomous terrestrial predators. Despite their use for centuries in traditional medicine, centipede venoms remain poorly studied. However, recent work indicates that centipede venoms are highly complex chemical arsenals that are rich in disulfide-constrained peptides that have novel pharmacology and three-dimensional structure. AREAS COVERED: This review summarizes what is currently known about centipede venom proteins, with a focus on disulfide-rich peptides that have novel or unexpected pharmacology that might be useful from a therapeutic perspective...
September 9, 2016: Expert Opinion on Drug Discovery
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