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cyclization peptides

Julio A Camarero
Cyclotides are fascinating microproteins (≈30-40 residues long) with a unique head-to-tail cyclized backbone, stabilized by three disulfide bonds forming a cystine knot. This unique topology makes them exceptionally stable to chemical, thermal and biological degradation compared to other peptides of similar size. Cyclotides have been also found to be highly tolerant to sequence variability, aside from the conserved residues forming the cystine knot, able to cross cellular membranes and modulate intracellular protein-protein interactions both in vitro and in vivo...
October 21, 2017: Bioorganic & Medicinal Chemistry Letters
Wei Zhang, Biao Zhong, Chi Zhang, Yukai Wang, Shang Guo, Congfeng Luo, Yulin Zhan
The ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) enzyme is a matrix-associated zinc metalloendopeptidase that plays an essential role in the degradation of cartilage aggrecan in arthritic diseases and has been recognized as one of the most primary targets for therapeutic intervention in osteoarthritis (OA). Here, we reported computational modeling of the atomic-level complex structure of ADAMTS4 with its cognate inhibitory protein TIMP3 based on high-resolution crystal template...
November 2, 2017: Bioorganic Chemistry
Alan James Cameron, Christopher J Squire, Patrick J B Edwards, Elena Harjes, Vijayalekshmi Sarojini
Herein we report the unique conformations adopted by linear and cyclic tetrapeptides (CTPs) containing 2-aminobenzoic acid (2-Abz) in solution and as single crystals. The crystal structure of the linear tetrapeptide H2N-D-Leu-D-Phe-2-Abz-D-Ala-COOH (1) reveals a novel planar peptidomimetic β-turn stabilized by three hydrogen bonds and is in agreement with its NMR structure in solution. While CTPs are often synthetically inaccessible or cyclize in poor yield, both 1 and its N-Me-D-Phe analogue (2) adopt pseudo-cyclic frameworks enabling near quantitative conversion to the corresponding CTPs 3 and 4...
November 2, 2017: Chemistry, An Asian Journal
Roland Hellinger, Kathrin Thell, Mina Vasileva, Taj Muhammad, Sunithi Gunasekera, Daniel Kümmel, Ulf Göransson, Christian W Becker, Christian W Gruber
Target deconvolution is one of the most challenging tasks in drug discovery, but a key step in drug development. In contrast to small molecules, there is a lack of validated and robust methodologies for target elucidation of peptides. In particular, it is difficult to apply these methods to cyclic and cysteine-stabilized peptides since they exhibit reduced amenability to chemical modification and affinity capture; however, such ribosomally synthesized and post-translationally modified peptide natural products are rich sources of promising drug candidates...
2017: Frontiers in Chemistry
Rania Soudy, Aarti Patel, Wen Fu, Kamaljit Kaur, David MacTavish, David Westaway, Rachel Davey, Jeffrey Zajac, Jack Jhamandas
INTRODUCTION: Amylin receptor serves as a portal for the expression of deleterious effects of amyloid β-protein (Aβ), a key pathologic hallmark of Alzheimer's disease. Previously, we showed that AC253, an amylin receptor antagonist, is neuroprotective against Aβ toxicity in vitro and abrogates Aβ-induced impairment of hippocampal long-term potentiation. METHODS: Amyloid precursor protein-overexpressing TgCRND8 mice received intracerebroventricularly AC253 for 5 months...
January 2017: Alzheimer's & Dementia: Translational Research & Clinical Interventions
Danielle A Guarracino, Alexis Oldfield, Kayla Gentile, Sara Martin, Dylan Nguyen, Gianna Barreto, Christopher Kouba
The development of peptide-based therapeutics is on the rise, with macrocyclic compounds providing the added stability and drug-like characteristics sought after. Currently, therapies and preventatives for pathogenic thrombosis target platelet interactions at the site of the clot and have many complications. Herein we describe novel cyclic peptides as moderate inhibitors of the protein-protein interaction between von Willebrand factor (vWF) and collagen that initiates blood clot formation. We based our designs on two known disulfide-containing, peptide-based inhibitors of the vWF-collagen interaction...
October 23, 2017: ChemMedChem
Liqin Liu, Jingli Xu, Jianquan Yang, Changjian Feng, Yubin Miao
The purpose of this study was to determine the metastatic melanoma imaging property of (99m)Tc(EDDA)-HYNIC-Aoc-Nle-CycMSHhex {hydrazinonicotinamide-8-aminooctanoic acid-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2}. HYNIC-Aoc-Nle-CycMSHhex was synthesized using fluorenylmethyloxy carbonyl (Fmoc) chemistry. The IC50 value of HYNIC-Aoc-Nle-CycMSHhex was 0.78 ± 0.13 nM for B16/F10 melanoma cells. (99m)Tc(EDDA)-HYNIC-Aoc-Nle-CycMSHhex displayed significantly higher uptake (14.26 ± 2.74 and 10.45 ± 2.31% ID/g) in B16/F10 metastatic melanoma-bearing lung than that in normal lung (0...
November 15, 2017: Bioorganic & Medicinal Chemistry Letters
Tyrslai M Williams, Rushikesh Sable, Sitanshu Singh, M Graça H Vicente, Seetharama Jois
Colorectal cancer (CRC) is the third most common solid internal malignancy among cancers. Early detection of cancer is key to increasing the survival rate of colorectal cancer patients. Overexpression of the EGFR protein is associated with CRC. We have designed a series of peptides that are highly specific for the extracellular domain of EGFR, based on our earlier studies on linear peptides. The previously reported linear peptide LARLLT, known to bind to EGFR, was modified with the goals of increasing its stability and its specificity towards EGFR...
October 20, 2017: Chemical Biology & Drug Design
Chayanon Ngambenjawong, Heather Gustafson, Meilyn Sylvestre, Suzie Pun
Peptides are a growing class of macromolecules used in pharmaceutics. The path toward clinical use of candidate peptides involves sequence optimization and cyclization for stability and affinity. For internalized peptides, tagging is also often required for intracellular trafficking studies, although fluorophore conjugation has been shown to impact peptide binding, permeability, and localization. Here, we report a strategy based on cysteine arylation with tetrafluoroterephthalonitrile (4F-2CN) that simultaneously cyclizes peptides and imparts fluorescence...
October 17, 2017: Chembiochem: a European Journal of Chemical Biology
Zhiliang Chen, Börje Sellergren, Xiantao Shen
In this work, we developed an efficient "molecularly imprinted polymer microzymes and inorganic magnetic nanozymes" synergistic catalysis strategy for the formation of disulfide bonds in peptides. The polymeric microzymes showed excellent selectivity toward the template peptide as well as the main reactant (linear peptide), and the Fe3O4 magnetic nanoparticle (MNP) nanozymes inhibited the intermolecular reaction during the formation of disulfide bonds in peptides. As a result, the integration of the two different artificial enzymes in one process facilitates the intramolecular cyclization in high product yields (59...
2017: Frontiers in Chemistry
Daniel Palmer, Juliana P L Gonçalves, Louise V Hansen, Boqian Wu, Helle Hald, Sanne Schoffelen, Frederik Diness, Sebastian T Le Quement, Thomas E Nielsen, Morten Meldal
The melanocortin receptor 4 (MC4R) subtype of the melanocortin receptor family is a target for therapeutics to ameliorate metabolic dysfunction. Endogenous MC4R agonists possess a critical pharmacophore (HFRW), and cyclization of peptide agonists often enhances potency. Thus, 17 cyclized peptides were synthesized by solid phase click chemistry to develop novel, potent, selective MC4R agonists. Using cAMP measurements and a transcriptional reporter assay, we observed that several constrained agonists generated by a cycloaddition reaction displayed high selectivity (223- to 467-fold) toward MC4R over MC3R and MC5R receptor subtypes without compromising agonist potency...
October 24, 2017: Journal of Medicinal Chemistry
Olivier Van der Poorten, Mouhamad Jida, Dirk Tourwé, Steven Ballet
BACKGROUND: Benzazepines received great attention in the field of medicinal chemistry since this scaffold has been recognized to belong to the important family of privileged templates. More specifically, the 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) is used as a core structure in a variety of constrained therapeutic peptide (turn) mimetics. Most of the synthetic approaches towards this template have focused on cyclizations which form the central 7-membered azepine ring. OBJECTIVE: Previous investigations in our group allowed an expansion of the substitution patterns in the 4-amino-benzazepin-3-one scaffold by introduction of methyl substituents at positions 4 and 5 of the azepinone ring system, but also to 1-aryl substituted compounds...
October 2, 2017: Medicinal Chemistry
Tao Bi, Yilong Li, Alexander Shekhtman, Julio A Camarero
We report the high-yield heterologous expression of bioactive θ-defensin RTD-1 inside Escherichia coli cells by making use of intracellular protein trans-splicing in combination with a high efficient split-intein. RTD-1 is a small backbone-cyclized polypeptide with three disulfide bridges and a natural inhibitor of anthrax lethal factor protease. Recombinant RTD-1 was natively folded and able to inhibit anthrax lethal factor protease. In-cell expression of RTD-1 was very efficient and yielded ≈0.7mg of folded RTD-1 per gram of wet E...
September 6, 2017: Bioorganic & Medicinal Chemistry
Michael T Ringel, Gerald Dräger, Thomas Brüser
The periplasmic conversion of ferribactin to pyoverdine is essential for siderophore biogenesis in fluorescent pseudomonads, such as pathogenic Pseudomonas aeruginosa or plant growth-promoting Pseudomonas fluorescens The non-ribosomal peptide ferribactin undergoes cyclizations and oxidations that result in the fluorophore, and a strictly conserved fluorophore-bound glutamic acid residue is converted to a range of variants, including succinamide, succinic acid, and α-ketoglutaric acid residues. We recently discovered that the pyridoxal phosphate-containing enzyme PvdN is responsible for the generation of the succinamide, which can be hydrolyzed to succinic acid...
November 10, 2017: Journal of Biological Chemistry
Cristina N Alexandru-Crivac, Christian Umeobika, Niina Leikoski, Jouni Jokela, Kirstie A Rickaby, André M Grilo, Peter Sjö, Alleyn T Plowright, Mohannad Idress, Eike Siebs, Ada Nneoyi-Egbe, Matti Wahlsten, Kaarina Sivonen, Marcel Jaspars, Laurent Trembleau, David P Fewer, Wael E Houssen
Macrocyclic peptides have promising therapeutic potential but the scaling up of their chemical synthesis is challenging. The cyanobactin macrocyclase PatGmac is an efficient tool for production but is limited to substrates containing 6-11 amino acids and at least one thiazoline or proline. Here we report a new cyanobactin macrocyclase that can cyclize longer peptide substrates and those not containing proline/thiazoline and thus allows exploring a wider chemical diversity.
September 26, 2017: Chemical Communications: Chem Comm
Stefanie Dobitz, Matthew R Aronoff, Helma Wennemers
Nature utilizes large biomolecules to fulfill tasks that require spatially well-defined arrangements at the molecular level such as electron transfer, ligand-receptor interactions, or catalysis. The creation of synthetic molecules that enable precise control over spacing and functionalization provides opportunities across diverse disciplines. Key requirements of functionalizable oligomeric scaffolds include the specific control of their molecular properties where the correct balance of flexibility and rigidity must be maintained in addition to the prerequisite of defined length...
October 17, 2017: Accounts of Chemical Research
Adam Přibylka, Viktor Krchňák
Here, we report the efficient solid-phase synthesis of N-propargyl peptides using Fmoc-amino acids and propargyl alcohol as key building blocks. Gold-catalyzed nucleophilic addition to the triple bond induced C-N bond formation, which triggered intramolecular cyclization, yielding 1,3,4-trisubstituted-5-methyl-3,4-dihydropyrazin-2(1H)-ones. Conformations of acyclic and constrained peptides were compared using a two-step conformer distribution analysis at the molecular mechanics level and density functional theory...
September 12, 2017: ACS Combinatorial Science
Matthew P Sarnowski, Kyle P Pedretty, Nicole Giddings, H Lee Woodcock, Juan R Del Valle
The stabilization of β-sheet secondary structure through peptide backbone modification represents an attractive approach to protein mimicry. Here, we present strategies toward stable β-hairpin folds based on peptide strand N-amination. Novel pyrazolidinone and tetrahydropyridazinone dipeptide constraints were introduced via on-resin Mitsunobu cyclization between α-hydrazino acid residues and a serine or homoserine side chain. Acyclic and cyclic N-amino peptide building blocks were then evaluated for their effect on β-hairpin stability in water using a GB1-derived model system...
August 31, 2017: Bioorganic & Medicinal Chemistry
Robert Michael Sgambelluri, Miranda O Smith, Jonathan D Walton
Cyclic peptides are promising compounds for new chemical biological tools and therapeutics due to their structural diversity, resistance to proteases, and membrane permeability. Amatoxins, the toxic principles of poisonous mushrooms, are biosynthesized on ribosomes as 35-mer precursor peptides which are ultimately converted to hydroxylated bicyclic octapeptides. The initial cyclization steps, catalyzed by a dedicated prolyl oligopeptidase (POPB), involves removal of the 10-amino acid leader sequence from the precursor peptide and transpeptidation to produce a monocyclic octapeptide intermediate...
September 2, 2017: ACS Synthetic Biology
Xiaosa Wu, Yen-Hua Huang, Quentin Kaas, Peta J Harvey, Conan K Wang, Han-Shen Tae, David J Adams, David J Craik
Conotoxin GeXIVA inhibits the α9α10 nicotinic acetylcholine receptor (nAChR) and is analgesic in animal models of pain. α-Conotoxins have four cysteines that can have three possible disulfide connectivities: globular (Cys(I)-Cys(III) and Cys(II)-Cys(IV)), ribbon (Cys(I)-Cys(IV) and Cys(II)-Cys(III)), or bead (Cys(I)-Cys(II) and Cys(III)-Cys(IV)). Native α-conotoxins preferably adopt the globular connectivity, and previous studies of α-conotoxins have focused on the globular isomers as the ribbon and bead isomers typically have lower potency at nAChRs than the globular form...
October 13, 2017: Journal of Biological Chemistry
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