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cyclization peptides

Kelsey R Schramma, Clarissa C Forneris, Alessio Caruso, Mohammad R Seyedsayamdost
Streptide is a ribosomally synthesized and post-translationally modified peptide with a unique cyclization motif consisting of an intramolecular lysine-tryptophan crosslink. Three radical SAM enzymes, StrB, AgaB, and SuiB from different Streptococci, have been shown to install this modification onto their respective precursor peptides in a leader-dependent fashion. Herein we conduct detailed investigations to differentiate between several plausible mechanistic proposals, specifically addressing radical versus electrophilic addition to the indole during crosslink formation, the role of substrate side-chains in binding in the enzyme active site, and the identity of the catalytic base in the reaction cycle...
January 10, 2018: Biochemistry
Tomoki Nakayoshi, Koichi Kato, Shuichi Fukuyoshi, Ohgi Takahashi, Eiji Kurimoto, Akifumi Oda
The l-α-Asp residues in peptides or proteins are prone to undergo nonenzymatic reactions to form l-β-Asp, d-α-Asp, and d-β-Asp residues via a succinimide five-membered ring intermediate. From these three types of isomerized aspartic acid residues, particularly d-β-Asp has been widely detected in aging tissue. In this study, we computationally investigated the cyclization of α- and β-Asp residues to form succinimide with dihydrogen phosphate ion as a catalyst (H2PO4-). We performed the study using B3LYP/6-31+G(d,p) density functional theory calculations...
January 3, 2018: Biochimica et Biophysica Acta
Stefan Verhoog, Choon Wee Kee, Yanlan Wang, Tanatorn Khotavivattana, Thomas C Wilson, Veerle Kersemans, Sean Smart, Matthew Tredwell, Benjamin G Davis, Veronique Emilie Gouverneur
The 18F-labeling of 5-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate, commonly referred to as the Umemoto reagent, has been accomplished applying a halogen exchange 18F-fluorination with 18F-fluoride, followed by oxidative cyclization with Oxone® and trifluoromethanesulfonic anhydride. This new 18F-reagent allows for the direct chemoselective 18F-labeling of unmodified peptides at the thiol cysteine residue.
January 5, 2018: Journal of the American Chemical Society
Rui-Yang Zhang, Parashar Thapa, Michael J Espiritu, Vinay Menon, Jon-Paul Bingham
Cyclic peptides and cyclotides are becoming common identities within the present efforts seen in peptide engineering - as we seek approaches to achieve potent biological activity, pharmacological selectivity, structurally stability and oral bioavailability. Yet this unique family of peptides has faced uncommon hurdles in their discovery, synthesis and bioengineering, retaining to characteristics that truly deviate these from their linear counterparts. In this mini-review we take a board spectrum approach to introduce this novel family of biomolecules and the troubles that they face in their sequence and disulfide connectivity assignment, together highlighting the present combined strategies involved in cyclic peptide/cyclotide synthesis and modification...
December 14, 2017: Bioorganic & Medicinal Chemistry
Putcha A N V Harita, Putcha Seshi Kumar, Shiva Krishna Reddy Guduru, Parameshwar Ravula, J N Narendra Sharath Chandra
A novel series of medium size (S)-3-alkyl-3,4,6,7-tetrahydro-1H-benzo[e][1,4]diazonine-2,5-dione (6a-f) analogues were synthesized from (E)-3-(2-nitrophenyl)acrylicacid (2) reacting with various amino acid esters using Di-isopropyl Carbodiimide as a coupling agent. The final cyclization is carried out by using reagent 1-Ethyl-3(3-dimethylaminopropyl) Carbodiimide Hydrochloride. The synthesized compounds have been supported by Mass, 1H-NMR and 13C-NMR. Further antibacterial studies were conducted, where some molecules are noticed with potent activity, especially molecule 6d shown highest activity which was also supported by molecular docking studies...
2017: EXCLI Journal
Rui Yang, Guojun Zhang, Furui Zhang, Zhanjiang Li, Chun Huang
The structural dynamics of membrane permeabilization are investigated systematically and compared between viral fusion peptides (VFPs) and antimicrobial peptides (AMPs). It is revealed that the permeabilization process can be divided into two phases: a fast motion phase in water (first phase) and a slow diffusion phase in lipid (second phase). Difference in peptide permeability to neutrally or weakly charged mammalian membrane and to negatively charged bacterial membrane is primarily determined by the first phase, which is dominated by the direct electrostatic interaction between peptide and the hydrophilic surface of membranes...
December 22, 2017: Biochimie
Tracy A Stone, Gregory B Cole, Huong Q Nguyen, Simon Sharpe, Charles M Deber
Cyclization has been recognized as a valuable technique for increasing the efficacy of small molecule and peptide therapeutics. Here we report the application of a hydrocarbon staple to a rationally-designed cationic antimicrobial peptide (CAP) that acquires increased membrane targeting and interaction vs. its linear counterpart. The previously-described CAP, 6K-F17 (KKKKKK-AAFAAWAAFAA-NH2) was used as the backbone for incorporation of an i to i + 4 helical hydrocarbon staple through olefin ring closing metathesis...
October 21, 2017: Bioorganic & Medicinal Chemistry
Wei-Jie Fang, Thomas F Murray, Jane V Aldrich
Kappa (κ) opioid receptor selective antagonists are useful pharmacological tools in studying κ opioid receptors and have potential to be used as therapeutic agents for the treatment of a variety of diseases including mood disorders and drug addiction. Arodyn (Ac[Phe1-3,Arg4,d-Ala8]Dyn A-(1-11)NH2) is a linear acetylated dynorphin A (Dyn A) analog that is a potent and selective κ opioid receptor antagonist (Bennett et al. J Med Chem 2002;45:5617-5619) and prevents stress-induced reinstatement of cocaine-seeking behavior following central administration (Carey et al...
November 21, 2017: Bioorganic & Medicinal Chemistry
Marcel Schmidt, Ana Toplak, Peter J L M Quaedflieg, Jan H van Maarseveen, Timo Nuijens
The recent advancement of peptide macrocycles as promising therapeutics creates a need for novel methodologies for their efficient synthesis and (large scale) production. Within this context, due to the favorable properties of biocatalysts, enzyme-mediated methodologies have gained great interest. Enzymes such as sortase A, butelase 1, peptiligase and omniligase-1 represent extremely powerful and valuable enzymatic tools for peptide ligation, since they can be applied to generate complex cyclic peptides with exquisite biological activity...
December 2017: Drug Discovery Today. Technologies
Alvard Antonyan, Dagmar Schlenzig, Stephan Schilling, Marcel Naumann, Svetlana Sharoyan, Sona Mardanyan, Hans-Ulrich Demuth
Compelling evidence suggests a crucial role of amyloid beta peptides (Aβ(1-40/42)) in the etiology of Alzheimer's disease (AD). The N-terminal truncation of Aβ(1-40/42) and their modification, e.g. by glutaminyl cyclase (QC), is expected to enhance the amyloid toxicity. In this work, the MALDI-TOF mass spectrometry application proved N-terminal cleavage of Aβ(1-40/42) by purified dipeptidyl peptidase IV (DPPIV) in vitro observed earlier. The subsequent transformation of resulted Aβ(3-40/42) to pE-Aβ(3-40/42) in QC catalyzed glutamate cyclization was manifested...
December 7, 2017: Neurochemistry International
Xiaoyu Zhang, Fei Wang, Qing Shen, Cao Xie, Yu Liu, Jun Pan, Weiyue Lu
The stability and binding affinity of targeting ligands play important roles in active targeting drug delivery. Herein LyP-1 peptide was used as a model peptide to investigate chemical-biology-based strategies in the design of peptide ligands for active targeting. LyP-1, a short peptide cyclized with a disulfide bond, can specifically bind to tumor cells and tumor lymphatics through the interaction with cell-surface protein p32/gC1qR. Lc(LyP-1), with the same sequence of LyP-1 by amide coupling, showed better cellular uptake and stability in blood in our previous research...
December 7, 2017: Molecular Pharmaceutics
Michael T Ringel, Gerald Draeger, Thomas Brüser
Pyoverdines are important siderophores that guarantee iron supply to important pathogenic and non-pathogenic pseudomonads in host habitats. A key characteristic of all pyoverdines is the fluorescent dihydroxyquinoline group that contributes two ligands to the iron complexes. Pyoverdines are derived from the non-ribosomally synthesized peptide ferribactin and their fluorophore is generated by periplasmic oxidation and cyclization reactions of D-tyrosine and L-diaminobutyric acid. The formation of the fluorophore is known to be driven by the periplasmic tyrosinase PvdP...
December 5, 2017: Journal of Biological Chemistry
Geert Hendrikx, Tilman M Hackeng, Rick van Gorp, Matthias Bauwens, Leon J Schurgers, Felix M Mottaghy, Mark J Post, Ingrid Dijkgraaf
As CD13 is selectively expressed in angiogenesis, it can serve as a target for molecular imaging tracers to noninvasively visualize angiogenic processes in vivo. The CD13-targeting moiety NGR was synthesized and cyclized by native chemical ligation (NCL) instead of disulfide bridging, leading to a cyclic peptide backbone: cyclo(Cys-Asn-Gly-Arg-Gly) (coNGR). Beside this new monomeric coNGR, a tetrameric NGR peptide co(NGR)4 was designed and synthesized. After radiolabeling, their in vitro and in vivo characteristics were determined...
2017: Contrast Media & Molecular Imaging
Rajiv Dahiya, Sunil Singh
The synthesis of a proline-rich cyclic heptapeptide, fanlizhicyclopeptide A (8), previously isolated from the fruits of Annona squamosa (sugar-apples), is described via coupling of tetrapeptide -prolyl--tyrosyl--leucyl--proline methyl ester with tripeptide Boc-glycyl--valyl--proline followed by cyclization of the linear fragment having seven amino acid units. Structure of the synthesized cyclooligopeptide was confirmed by the means of chemical and spectroscopic methods including FTIR, 1H NMR, 13C NMR, FABMS and further, subjected to the anthelmintic, antibacterial and the antifungal activity studies...
2017: Iranian Journal of Pharmaceutical Research: IJPR
Joel Castro, Luke Grundy, Annemie Deiteren, Andrea M Harrington, Tracey O'Donnell, Jessica Maddern, Jessi Moore, Sonia Garcia-Caraballo, Grigori Y Rychkov, Rilei Yu, Quentin Kaas, David J Craik, David J Adams, Stuart M Brierley
BACKGROUND AND PURPOSE: Patients with Irritable Bowel Syndrome suffer from chronic visceral pain (CVP); however, limited analgesic therapeutic options are currently available. We have shown that α-conotoxin Vc1.1-induced activation of GABAB receptors on the peripheral endings of colonic afferents reduces nociceptive signalling from the viscera. However, the analgesic efficacy of more stable, cyclized versions of Vc1.1 on CVP remains to be determined. EXPERIMENTAL APPROACH: Using ex vivo colonic afferent preparations, we determined the inhibitory actions of cyclized Vc1...
November 30, 2017: British Journal of Pharmacology
Jan Herman Van Maarseveen, Peter Timmerman, Gaston Richelle, Sumeet Ori, Henk Hiemstra
We report a one-pot ligation-cyclization technology for the rapid and clean conversion of linear peptides into tricyclic peptides using tetravalent scaffolds containing two benzyl bromides and two alkyne functionalities that react via CLIPS/CuAAC reactions with cysteines and azides in the peptide. Flexibility in the scaffolds is key to the exclusive formation of isomerically pure products, since flexible T41 and T42-scaffolds promote formation of single isomeric tricycles in most cases, while rigid T43 and T44-scaffolds resist formation of clean products...
November 29, 2017: Angewandte Chemie
Kalkena Sivanesam, Brandon L Kier, Samuel D Whedon, Champak Chatterjee, Niels H Andersen
Designing new antimicrobial peptides (AMPs) focuses heavily on the activity of the peptide and less on the elements that stabilize the secondary structure of these peptides. Studies have shown that improving the structure of naturally occurring AMPs can affect activity and so here we explore the relationship between structure and activity of two non-naturally occurring AMPs. We have used a backbone-cyclized peptide as a template and designed an uncyclized analogue of this peptide that has antimicrobial activity...
December 2017: Journal of Peptide Science: An Official Publication of the European Peptide Society
Madeleine Peschke, Clara Brieke, Michael Heimes, Max J Cryle
The biosynthesis of the glycopeptide antibiotics (GPAs) - which include teicoplanin and vancomycin - is a complex enzymatic process relying on the interplay of non-ribosomal peptide synthesis and a Cytochrome P450-mediated cyclization cascade. This unique cyclization cascade generates the highly crosslinked state of these non-ribosomal peptides, which is crucial for their antimicrobial activity. Given that these essential oxidative transformations occur whilst the peptide remains bound to the terminal module of the non-ribosomal peptide synthetase (NRPS) machinery, it is important to assess the selectivity of the terminal thioesterase (TE) domain and how this domain contributes to the maintenance of an efficient biosynthetic pathway whilst at the same time ensuring GPA maturation is completed...
December 1, 2017: ACS Chemical Biology
(no author information available yet)
The clavine alkaloids produced by the fungi of the Aspergillaceae and Arthrodermatacea families differ from the ergot alkaloids produced by Claviceps and Neotyphodium. The clavine alkaloids lack the extensive peptide chain modifications that occur in lysergic acid derived ergot alkaloids. Both clavine and ergot alkaloids arise from the condensation of tryptophan and dimethylallylpyrophosphate by the action of the dimethylallyltryptophan synthase. The first five steps of the biosynthetic pathway that convert tryptophan and dimethylallyl-pyrophosphate (DMA-PP) in chanoclavine-1-aldehyde are common to both clavine and ergot alkaloids...
November 24, 2017: Genes
Chengcheng Zhang, Kuo-Shyan Lin, François Bénard
Melanoma is a deadly disease at late metastatic stage, and early diagnosis and accurate staging remain the key aspects for managing melanoma. The melanocortin 1 receptor (MC1 R) is overexpressed in primary and metastatic melanomas, and its endogenous ligand, the α-melanocyte-stimulating hormone (αMSH), has been extensively studied for the development of MC1 R-targeted molecular imaging and therapy of melanoma. Natural αMSH is not well suited for this purpose due to low stability in vivo. Unnatural amino acid substitutions substantially stabilized the peptide, while cyclization via lactam bridge and metal coordination further improved binding affinity and stability...
January 2017: Molecular Imaging
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