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cyclization peptides

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https://www.readbyqxmd.com/read/28318942/cyclic-mu-opioid-receptor-ligands-containing-multiple-n-methylated-amino-acid-residues
#1
Anna Adamska-Bartłomiejczyk, Anna Janecka, Márton Richárd Szabó, Maria Camilla Cerlesi, Girolamo Calo, Alicja Kluczyk, Csaba Tömböly, Attila Borics
In this study we report the in vitro activities of four cyclic opioid peptides with various sequence length/macrocycle size and N-methylamino acid residue content. N-Methylated amino acids were incorporated and cyclization was employed to enhance conformational rigidity to various extent. The effect of such modifications on ligand structure and binding properties were studied. The pentapeptide containing one endocyclic and one exocyclic N-methylated amino acid displayed the highest affinity to the mu-opioid receptor...
March 7, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28302013/multicyclic-peptides-as-scaffolds-for-the-development-of-tumor-targeting-agents
#2
Anastasia Loktev, Uwe Haberkorn, Walter Mier
The lack of specificity of traditional cytotoxic drugs triggers the development of anticancer agents with high selectivity to tumor-specific proteins. The unveiling of target structures such as EGFR or Her2 allows the focused development of novel therapies and has strongly advanced tumor treatment. Tumor-specific high-affinity ligands can be identified by using display techniques such as phage, yeast surface, ribosome and mRNA display. These techniques enable the screening of huge libraries, consequently providing a valuable alternative to rational drug development...
March 16, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28298600/dengue-virus-ns2b-ns3-protease-inhibitors-exploiting-the-prime-side
#3
Kuan-Hung Lin, Akbar Ali, Linah Rusere, Djade I Soumana, Nese Kurt Yilmaz, Celia A Schiffer
The mosquito-transmitted dengue virus (DENV) infects millions of people in tropical and sub-tropical regions. Maturation of DENV particles requires proper cleavage of the viral polyprotein, including processing 8 of the 13 substrate cleavage sites by dengue NS2B-S3 protease. With no available direct-acting antiviral targeting DENV, NS2-S3 protease is a promising target for inhibitor design. Current design efforts focus on the nonprime side of the DENV protease active site, resulting in highly hydrophilic and nonspecific scaffolds...
March 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28273421/a-mechanistic-model-for-the-aziridine-aldehyde-driven-macrocyclization-of-peptides
#4
Lee Belding, Serge Zaretsky, Andrei K Yudin, Travis Dudding
Aziridine aldehyde-driven macrocyclization of peptides is a powerful tool for the construction of biologically active macrocycles. While this process has been used to generate diverse collections of cyclic molecules, its mechanistic underpinnings have remained unclear. To enable progress in this area we have carried out a mechanistic study, which suggests that the cyclization owes its efficiency to a combination of electrostatic attraction between termini of a discrete nitrilium ion intermediate and intramolecular hydrogen bonding...
March 8, 2017: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28245769/macrocyclic-antimicrobial-peptides-engineered-from-%C3%AF-conotoxin
#5
Xinya Hemu, James Tam
The potent calcium channel blocker ω-conotoxin MVIIA is a linear cystine-knot peptide with multiple basic amino acids at both termini. This work shows that macrocyclization of MVIIA linking two positive-charge terminal clusters as a contiguous segment converts a conotoxin into an antimicrobial peptide. In addition, conversion of disulfide bonds to amino butyric acids improved the antimicrobial activity of the cyclic analogs. Ten macrocyclic analogs, with or without disulfide bonds, were prepared by both Boc and Fmoc chemistry using native chemical ligation...
October 27, 2016: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28240912/domain-targeted-metabolomics-delineates-the-heterocycle-assembly-steps-of-colibactin-biosynthesis
#6
Eric P Trautman, Alan R Healy, Emilee E Shine, Seth B Herzon, Jason M Crawford
Modular polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs) comprise giant multidomain enzymes responsible for the "assembly line" biosynthesis of many genetically encoded small molecules. Site-directed mutagenesis, protein biochemical, and structural studies have focused on elucidating the catalytic mechanisms of individual multidomain proteins and protein domains within these megasynthases. However, probing their functions at the cellular level typically has invoked the complete deletion (or overexpression) of multidomain-encoding genes or combinations of genes and comparing those mutants with a control pathway...
March 10, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28230996/a-facile-n-mercaptoethoxyglycinamide-mega-linker-approach-to-peptide-thioesterification-and-cyclization
#7
Patrick M M Shelton, Caroline E Weller, Champak Chatterjee
The C-terminal electrophilic activation of peptides by α-thioesterification requires strongly acidic conditions or complex chemical manipulations, which ultimately limit functional group compatibility and broad utility. Herein, we report a readily accessible N-mercaptoethoxyglycinamide (MEGA) solid-phase linker for the facile synthesis of latent peptide α-thioesters. Incubating peptide-MEGA sequences with 2-mercaptoethanesulfonic acid at mildly acidic pH yielded α-thioesters that were directly used in NCL without purification...
March 9, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28222263/reaction-mechanism-of-covalent-modification-of-phosphatidylethanolamine-lipids-by-reactive-aldehydes-4-hydroxy-2-nonenal-and-4-oxo-2-nonenal
#8
Katarina Vazdar, Danijela Vojta, Davor Margetić, Mario Vazdar
4-Hydroxy-2-nonenal (HNE) and 4-oxo-2-nonenal (ONE) are biologically important reactive aldehydes formed during oxidative stress in phospholipid bilayers. They are highly reactive species due to presence of several reaction centers and can react with amino acids in peptides and proteins, as well as phosphoethanolamine (PE) lipids, thus modifying their biological activity. The aim of this work is to study in a molecular detail the reactivity of HNE and ONE toward PE lipids in a simplified system containing only lipids and reactive aldehydes in dichloromethane as an inert solvent...
March 6, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28218515/chlorinated-glycopeptide-antibiotic-peptide-precursors-improve-cytochrome-p450-catalyzed-cyclization-cascade-efficiency
#9
Madeleine Peschke, Clara Brieke, Rob J A Goode, Ralf B Schittenhelm, Max J Cryle
The activity of glycopeptide antibiotics (GPAs) depends upon important structural modifications to their precursor heptapeptide backbone: specifically, the cytochrome P450-catalyzed oxidative cross-linking of aromatic side chains as well as the halogenation of specific residues within the peptide. The timing of halogenation and its effect on the cyclization of the peptide are currently unclear. Our results show that chlorination of peptide precursors improves their processing by P450 enzymes in vitro, which provides support for GPA halogenation occurring prior to peptide cyclization during nonribosomal peptide synthesis...
February 24, 2017: Biochemistry
https://www.readbyqxmd.com/read/28212041/simultaneous-cyclization-and-derivatization-of-peptides-using-cyclopentenediones
#10
Omar Brun, Lewis J Archibald, Jordi Agramunt, Enrique Pedroso, Anna Grandas
Unprotected linear peptides containing N-terminal cysteines and another cysteine residue can be simultaneously cyclized and derivatized using 2,2-disubstituted cyclopentenediones. High yields of cyclic peptide conjugates may be obtained in short reaction times using only a slight excess of the cyclopentenedione moiety under TEMPO catalysis and in the presence of LiCl.
February 17, 2017: Organic Letters
https://www.readbyqxmd.com/read/28191919/lysine-tryptophan-crosslinked-peptides-produced-by-radical-sam-enzymes-in-pathogenic-streptococci
#11
Kelsey R Schramma, Mohammad R Seyedsayamdost
Macrocycles represent a common structural framework in many naturally occurring peptides. Several strategies exist for macrocyclization, and the enzymes that incorporate them are of great interest, as they enhance our repertoire for creating complex molecules. We recently discovered a new peptide cyclization reaction involving a crosslink between the side chains of lysine and tryptophan that is installed by a radical SAM enzyme. Herein, we characterize relatives of this metalloenzyme from the pathogens Streptococcus agalactiae and Streptococcus suis...
March 3, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28165720/intein-promoted-cyclization-of-aspartic-acid-flanking-the-intein-leads-to-atypical-n-terminal-cleavage
#12
Christopher J Minteer, Nicolle M Siegart, Kathryn M Colelli, Xinyue Liu, Robert J Linhardt, Chunyu Wang, Alvin V Gomez, Julie N Reitter, Kenneth V Mills
Protein splicing is a post-translational reaction facilitated by an intein, or intervening protein, which involves the removal of the intein and the ligation of the flanking polypeptides, or exteins. A DNA polymerase II intein from Pyrococcus abyssi (Pab PolII intein) can promote protein splicing in vitro on incubation at high temperature. Mutation of active site residues Cys1, Gln185, and Cys+1 to Ala results in an inactive intein precursor, which cannot promote the steps of splicing, including cleavage of the peptide bond linking the N-extein and intein (N-terminal cleavage)...
February 15, 2017: Biochemistry
https://www.readbyqxmd.com/read/28165293/anticancer-activities-of-bovine-and-human-lactoferricin-derived-peptides
#13
Mauricio Arias, Ashley L Hilchie, Evan F Haney, Jan G M Bolscher, M Eric Hyndman, Robert E W Hancock, Hans J Vogel
Lactoferrin (LF) is a mammalian host defense glycoprotein with diverse biological activities. Peptides derived from the cationic region of LF possess cytotoxic activity against cancer cells in vitro and in vivo. Bovine lactoferricin (LFcinB), a peptide derived from bovine LF (bLF), exhibits broad-spectrum anticancer activity, while a similar peptide derived from human LF (hLF) is not as active. In this work, several peptides derived from the N-terminal regions of bLF and hLF were studied for their anticancer activities against leukemia and breast-cancer cells, as well as normal peripheral blood mononuclear cells...
February 2017: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
https://www.readbyqxmd.com/read/28153544/post-translationally-modified-frog-skin-derived-antimicrobial-peptides-are-effective-against-aeromonas-sobria
#14
Vineethkumar Tv, Asha R, Shyla G, Sanil George
Antimicrobial peptides (brevinin1 HYba1 and brevinin1 HYba2) identified from the skin secretion of an endemic frog species of Western Ghats were studied against fish pathogens. Post-translational modifications such as c-terminal amidation and cyclization of the peptides were enhanced on the activity against Aeromonas sobria. Based on the Minimum inhibitory concentration (3 μM), cyclic amidated brevinin Hyba2 was identified as the most promising antimicrobial agent against A. sobria and can be developed further as a lead drug molecule...
March 2017: Microbial Pathogenesis
https://www.readbyqxmd.com/read/28151653/full-sequence-amino-acid-scanning-of-%C3%AE-defensin-rtd-1-yields-a-potent-anthrax-lethal-factor-protease-inhibitor
#15
Yilong Li, Andrew Gould, Teshome Aboye, Tao Bi, Leonard Breindel, Alexander Shekhtman, Julio A Camarero
θ-Defensin RTD-1 is a noncompetitive inhibitor of anthrax lethal factor (LF) protease (IC50 = 390 ± 20 nM, Ki = 365 ± 20 nM) and a weak inhibitor of other mammalian metalloproteases such as TNFα converting enzyme (TACE) (Ki = 4.45 ± 0.48 μM). Using full sequence amino acid scanning in combination with a highly efficient "one-pot" cyclization-folding approach, we obtained an RTD-1-based peptide that was around 10 times more active than wild-type RTD-1 in inhibiting LF protease (IC50 = 43 ± 3 nM, Ki = 18 ± 1 nM)...
February 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28148910/intein-mediated-backbone-cyclization-of-vp1-protein-enhanced-protection-of-cvb3-induced-viral-myocarditis
#16
Xingmei Qi, Sidong Xiong
CVB3 is a common human pathogen to be highly lethal to newborns and causes viral myocarditis and pancreatitis in adults. However, there is no vaccine available for clinical use. CVB3 capsid protein VP1 is an immunodominant structural protein, containing several B- and T-cell epitopes. However, immunization of mice with VP1 protein is ineffective. Cyclization of peptide is commonly used to improve their in vivo stability and biological activity. Here, we designed and synthesizd cyclic VP1 protein by using engineered split Rma DnaB intein and the cyclization efficiency was 100% in E...
February 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28135077/mechanistic-understanding-of-lanthipeptide-biosynthetic-enzymes
#17
Lindsay M Repka, Jonathan R Chekan, Satish K Nair, Wilfred A van der Donk
Lanthipeptides are ribosomally synthesized and post-translationally modified peptides (RiPPs) that display a wide variety of biological activities, from antimicrobial to antiallodynic. Lanthipeptides that display antimicrobial activity are called lantibiotics. The post-translational modification reactions of lanthipeptides include dehydration of Ser and Thr residues to dehydroalanine and dehydrobutyrine, a transformation that is carried out in three unique ways in different classes of lanthipeptides. In a cyclization process, Cys residues then attack the dehydrated residues to generate the lanthionine and methyllanthionine thioether cross-linked amino acids from which lanthipeptides derive their name...
January 30, 2017: Chemical Reviews
https://www.readbyqxmd.com/read/28132916/characterization-of-ligand-binding-to-melanocortin-4-receptors-using-fluorescent-peptides-with-improved-kinetic-properties
#18
Reet Link, Santa Veiksina, Ago Rinken, Sergei Kopanchuk
Melanocortin 4 (MC4) receptors are important drug targets as they regulate energy homeostasis, eating behaviour and sexual functions. The ligand binding process to these G protein-coupled receptors is subject to considerable complexity. Different steps in the complex dynamic regulation can be characterized by ligand binding kinetics. Optimization of these kinetic parameters in terms of on-rate and residence time can increase the rapid onset of drug action and reduce off-target effects. Fluorescence anisotropy (FA) is one of the homogeneous fluorescence-based assays that enable continuous online monitoring of ligand binding kinetics...
January 26, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28122173/structure-based-derivation-of-peptide-inhibitors-to-target-tgf-%C3%AE-1-receptor-for-the-suppression-of-hypertrophic-scarring-fibroblast-activation
#19
Huan Hu, Songlin Yang, Jianghong Zhang, Guangyu Mao
The intermolecular recognition and interaction between human transforming growth factor β-1 (TGF-β1) and its cognate receptor TβRII have been implicated in the pathological condition of hypertrophic scarring (HS). Here, we attempted to rationally derive peptide inhibitors from the complex interface of TGF-β1 with TβRII to disrupt such interaction for the suppression of fibroblast activation involved in HS. A synthetic strategy that integrated computational design and fluorescence-based assay was described to examine the structural basis and energetic property of TGF-β1-TβRII crystal structure, from which a small peptide segment in the complex binding site was stripped artificially...
January 25, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28096492/identification-of-glutaminyl-cyclase-genes-involved-in-pyroglutamate-modification-of-fungal-lignocellulolytic-enzymes
#20
Vincent W Wu, Craig M Dana, Anthony T Iavarone, Douglas S Clark, N Louise Glass
The breakdown of plant biomass to simple sugars is essential for the production of second-generation biofuels and high-value bioproducts. Currently, enzymes produced from filamentous fungi are used for deconstructing plant cell wall polysaccharides into fermentable sugars for biorefinery applications. A post-translational N-terminal pyroglutamate modification observed in some of these enzymes occurs when N-terminal glutamine or glutamate is cyclized to form a five-membered ring. This modification has been shown to confer resistance to thermal denaturation for CBH-1 and EG-1 cellulases...
January 17, 2017: MBio
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