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Helical cyclic peptide

Yannan Zhao, Luke J Leman, Debra J Search, Ricardo A Garcia, David A Gordon, Bruce E Maryanoff, M Reza Ghadiri
There is great interest in developing new modes of therapy for atherosclerosis to treat coronary heart disease and stroke, particularly ones that involve modulation of high-density lipoproteins (HDLs). Here, we describe a new supramolecular chemotype for altering HDL morphology and function. Guided by rational design and SAR-driven peptide sequence enumerations, we have synthesized and determined the HDL remodeling activities of over 80 cyclic d,l-α-peptides. We have identified a few distinct sequence motifs that are effective in vitro in remodeling human and mouse plasma HDLs to increase the concentration of lipid-poor pre-beta HDLs, which are key initial acceptors of cholesterol in the reverse cholesterol transport (RCT) process, and concomitantly promote cholesterol efflux from macrophage cells...
June 28, 2017: ACS Central Science
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
Makoto Oba, Masayuki Kunitake, Takuma Kato, Atsushi Ueda, Masakazu Tanaka
Cell-penetrating peptides are receiving increasing attention as drug delivery tools, and the search for peptides with high cell-penetrating ability and negligible cytotoxicity has become a critical research topic. Herein, cyclic α,α-disubstituted α-amino acids were introduced into arginine-rich peptides and an additional staple was provided in the side chain. The peptides designed in the present study showed more enhanced and prolonged cell-penetrating abilities than an arginine nonapeptide due to high resistance to protease and conformationally stable helical structures...
July 19, 2017: Bioconjugate Chemistry
Marta Ruiz-Santaquiteria, Pedro A Sánchez-Murcia, Miguel A Toro, Héctor de Lucio, Kilian Jesús Gutiérrez, Sonia de Castro, Filipa A C Carneiro, Federico Gago, Antonio Jiménez-Ruiz, María-José Camarasa, Sonsoles Velázquez
A series of 9-mer and 13-mer amide-bridged cyclic peptides derived from the linear prototype Ac-PKIIQSVGIS-Nle-K-Nle-NH2 (Toro et al. ChemBioChem2013) has been designed and synthesized by introduction of the lactam between amino acid side chains that are separated by one helical turn (i, i+4). All of these compounds were tested in vitro as both dimerization and enzyme inhibitors of Leishmania infantum trypanothione reductase (Li-TryR). Three of the 13-mer cyclic peptide derivatives (3, 4 and 6) inhibited the oxidoreductase activity of Li-TryR in the low micromolar range and they also disrupted enzyme dimerization...
April 13, 2017: European Journal of Medicinal Chemistry
Marco Gerolin, Mirco Zerbetto, Alessandro Moretto, Fernando Formaggio, Claudio Toniolo, Martin van Son, Maryam Hashemi Shabestari, Martina Huber, Paolo Calligari, Antonino Polimeno
We address the interpretation, via an integrated computational approach, of the experimental continuous-wave electron paramagnetic resonance (cw-EPR) spectra of a complete set of conformationally highly restricted, stable 310-helical peptides from hexa- to nonamers, each bis-labeled with nitroxide radical-containing TOAC (4-amino-1-oxyl-2,2,6,6-tetramethylpiperidine-4-carboxylic acid) residues. The usefulness of TOAC for this type of analysis has been shown already to be due to its cyclic piperidine side chain, which is rigidly connected to the peptide backbone α-carbon...
May 4, 2017: Journal of Physical Chemistry. B
Abdulselam Adam, Gebhard Haberhauer, Christoph Wölper
Cyclic oligomers of azole peptides were isolated from a multitude of marine organisms and were used for a large number of molecular machines. As shown previously, oligomers derived from achiral imidazole amino acids fold into canonical helices. Here we show that a minor change, the introduction of a methyl group in the δ position, results in a significant change in the secondary structure of the corresponding oligomers. Instead of a canonical helix, a noncanonical herringbone helix is formed. In the latter, the slope along the helix changes its sign at least twice per turn...
April 12, 2017: Journal of Organic Chemistry
Annaleizle Ferranco, Shibaji Basak, Alan Lough, Heinz-Bernhard Kraatz
This study presents a few bis(histidine) ligands working to build a small peptidic model system of zinc structural sites. Ferrocene-peptide conjugates Fc[CO-His(Trt)-His(Trt)-OMe]2 (3), Fc[CO-His(Trt)-Asp(OMe)-OMe]2 (4), and Fc[CO-His(Trt)-Glu(OMe)-OMe]2 (5) were synthesized and characterized spectroscopically. (1)H-NMR and IR spectroscopic studies reveal hydrogen bonding interactions and while more detailed circular dichroism studies show a 1,2'-P helical "Herrick conformation" for Fc-conjugates 4 and 5, we discovered M-helical chirality in Fc-peptide 3...
March 28, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
Chinmayee Mohapatra, Manas Kumar Jagdev, Dileep Vasudevan
The caseinolytic protease machinery associated chaperone protein ClpC is known to be present in bacteria, plants and other eukaryotes, whereas ClpD is unique to plants. Plant ClpC and ClpD proteins get localized into chloroplast stroma. Herein, we report high resolution crystal structures of the N-terminal domain of Arabidopsis thaliana ClpC1 and ClpD. Surprisingly, AtClpD, but not AtClpC1, deviates from the typical N-terminal repeat domain organization of known Clp chaperones and have only seven α-helices, instead of eight...
March 13, 2017: Scientific Reports
Flavia A Mercurio, Marilisa Leone
BACKGROUND: Eph receptors play important functions in developmental processes and diseases and among them EphA2 is well known for its controversial role in cancer. Drug discovery strategies are mainly centered on EphA2 extracellular ligand-binding domain however, the receptor also contains a largely unexplored cytosolic Sam (Sterile alpha motif) domain at the C-terminus. EphA2-Sam binds the Sam domain from the lipid phosphatase Ship2 and the first Sam domain of Odin. Sam-Sam interactions may be important to regulate ligand-induced receptor endocytosis and degradation i...
2016: Current Medicinal Chemistry
Inhye Kim, Eun Hee Han, Jooyeon Ryu, Jin-Young Min, Hyungju Ahn, Young-Ho Chung, Eunji Lee
We report a simple and facile strategy for the preparation of multifunctional nanoparticles with programmable properties using self-assembly of precisely designed block amphiphiles in an aqueous solution-state. Versatile, supramolecular nanoplatform for personalized needs, particularly-theranostics, was fabricated by coassembly of peptide amphiphiles (PAs) in aqueous solution, replacing time-consuming and inaccessible chemical synthesis. Fibrils, driven by the assembly of hydrophobic β-sheet-forming peptide block, were utilized as a nanotemplate for drug loading within their robust core...
October 10, 2016: Biomacromolecules
Basavalingappa Vasantha, Gijo George, Srinivasarao Raghothama, Padmanabhan Balaram
Novel helical, structures unprecedented in the chemistry of α-polypeptides, may be found in polypeptides containing β and γ amino acids. The structural characterization of C12 and C14 -helices in oligo β-peptides was originally achieved using conformationally constrained cyclic β-residues. This study explores the conformational characteristics of proteinogenic β(3) residues in homooligomeric sequences and addresses the issue of inducing a transition between C14 and C12 helices by the introduction of a guest α-residue...
January 2017: Biopolymers
Brian F Fisher, Samuel H Gellman
α/γ-Peptide foldamers containing either γ(4)-amino acid residues or ring-constrained γ-amino acid residues have been reported to adopt 12-helical secondary structure in nonpolar solvents and in the solid state. These observations have engendered speculation that the seemingly flexible γ(4) residues have a high intrinsic helical propensity and that residue-based preorganization may not significantly stabilize the 12-helical conformation. However, the prior studies were conducted in environments that favor intramolecular H-bond formation...
August 31, 2016: Journal of the American Chemical Society
Atsushi Ueda, Tomohiro Umeno, Mitsunobu Doi, Kengo Akagawa, Kazuaki Kudo, Masakazu Tanaka
Helical peptide foldamer catalyzed Michael addition reactions of nitroalkane or dialkyl malonate to α,β-unsaturated ketones are reported along with the mechanistic considerations of the enantio-induction. A wide variety of α,β-unsaturated ketones, including β-aryl, β-alkyl enones, and cyclic enones, were found to be catalyzed by the helical peptide to give Michael adducts with high enantioselectivities (up to 99%). On the basis of X-ray crystallographic analysis and depsipeptide study, the amide protons, N(2)-H and N(3)-H, at the N terminus in the α-helical peptide catalyst were crucial for activating Michael donors, while the N-terminal primary amine activated Michael acceptors through the formation of iminium ion intermediates...
August 5, 2016: Journal of Organic Chemistry
Sharareh Eskandari, Thalia Guerin, Istvan Toth, Rachel J Stephenson
Self-assembled peptides have shown outstanding characteristics for vaccine delivery and drug targeting. Peptide molecules can be rationally designed to self-assemble into specific nanoarchitectures in response to changes in their assembly environment including: pH, temperature, ionic strength, and interactions between host (drug) and guest molecules. The resulting supramolecular nanostructures include nanovesicles, nanofibers, nanotubes, nanoribbons, and hydrogels and have a diverse range of mechanical and physicochemical properties...
June 26, 2016: Advanced Drug Delivery Reviews
Yosuke Demizu, Mitsunobu Doi, Hiroko Yamashita, Takashi Misawa, Makoto Oba, Masaaki Kurihara, Hiroshi Suemune, Masakazu Tanaka
A single chiral cyclic α,α-disubstituted amino acid with side-chain methoxymethyl (MOM) protecting groups, (3S,4S)-1-amino-(3,4-dimethoxymethoxy)cyclopentanecarboxylic acid [(S, S)-Ac5 c(dOMOM) ], or side-chain hydroxy groups, (3S,4S)-1-amino-(3,4-dihydroxy)cyclopentanecarboxylic acid [(S, S)-Ac5 c(dOH) ], was attached to the N-terminal or C-terminal position of α-aminoisobutyric acid (Aib) tetrapeptide segments; i.e., we designed and synthesized four pentapeptides, Cbz-[(S, S)-Ac5 c(dOMOM) ]-(Aib)4 -OEt (1), Cbz-[(S, S)-Ac5 c(dOH) ]-(Aib)4 -OEt (2), Cbz-(Aib)4 -[(S, S)-Ac5 c(dOMOM) ]-OMe (3), and Cbz-(Aib)4 -[(S, S)-Ac5 c(dOH) ]-OMe (4)...
September 2016: Biopolymers
Huy N Hoang, Russell W Driver, Renée L Beyer, Timothy A Hill, Aline D de Araujo, Fabien Plisson, Rosemary S Harrison, Lena Goedecke, Nicholas E Shepherd, David P Fairlie
Cyclic pentapeptides (e.g. Ac-(cyclo-1,5)-[KAXAD]-NH2 ; X=Ala, 1; Arg, 2) in water adopt one α-helical turn defined by three hydrogen bonds. NMR structure analysis reveals a slight distortion from α-helicity at the C-terminal aspartate caused by torsional restraints imposed by the K(i)-D(i+4) lactam bridge. To investigate this effect on helix nucleation, the more water-soluble 2 was appended to N-, C-, or both termini of a palindromic peptide ARAARAARA (≤5 % helicity), resulting in 67, 92, or 100 % relative α-helicity, as calculated from CD spectra...
July 11, 2016: Angewandte Chemie
Dale F Kreitler, David E Mortenson, Katrina T Forest, Samuel H Gellman
Synthetic peptides that contain backbone modifications but nevertheless adopt folded structures similar to those of natural polypeptides are of fundamental interest and may provide a basis for biomedical applications. Such molecules can, for example, mimic the ability of natural prototypes to bind to specific target macromolecules but resist degradation by proteases. We have previously shown that oligomers containing mixtures of α- and β-amino acid residues ("α/β-peptides") can mimic the α-helix secondary structure, and that properly designed α/β-peptides can bind to proteins that evolved to bind to α-helical partners...
May 25, 2016: Journal of the American Chemical Society
Frederick Harris, Saurabh Prabhu, Sarah R Dennison, Timothy J Snape, Robert Lea, Manuela Mura, David A Phoenix
It is becoming increasingly clear that plants ranging across the plant kingdom produce anionic host defence peptides (AHDPs) with potent activity against a wide variety of human cancers cells. In general, this activity involves membrane partitioning by AHDPs, which leads to membranolysis and / or internalization to attack intracellular targets such as DNA. Several models have been proposed to describe these events including: the toroidal pore and Shai-Matsuzaki-Huang mechanisms but, in general, the mechanisms underpinning the membrane interactions and anticancer activity of these peptides are poorly understood...
2016: Protein and Peptide Letters
Yan Shi, Peng Teng, Peng Sang, Fengyu She, Lulu Wei, Jianfeng Cai
The development of sequence-specific peptidomimetics has led to a variety of fascinating discoveries in chemical biology. Many peptidomimetics can mimic primary, secondary, and even tertiary structure of peptides and proteins, and because of their unnatural backbones, they also possess significantly enhanced resistance to enzymatic hydrolysis, improved bioavailability, and chemodiversity. It is known that peptide nucleic acids (PNAs) are peptidic sequences developed for the mimicry of nucleic acids; however, their unique backbone as the molecular scaffold of peptidomimetics to mimic structure and function of bioactive peptides has not been investigated systematically...
March 15, 2016: Accounts of Chemical Research
Makoto Oba, Hikaru Nonaka, Mitsunobu Doi, Masakazu Tanaka
A conformational analysis of peptides having dipropylglycine (Dpg) or 1-aminocycloheptanecarboxylic acid (Ac7 c) within L-leucine (Leu) residues was conducted in solution and in a crystal state. Dpg and Ac7 c had similar structures with acyclic and cyclic side chains, respectively. FT-IR, (1) H NMR, and CD spectra measurements revealed that the preferred conformations of Dpg- and Ac7 c-containing L-Leu peptides in solution were similar; both had a right-handed (P) 310 -helix. The Dpg-containing octapeptide adopted a right-handed (P) α-helix in the crystal state...
January 22, 2016: Biopolymers
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