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https://www.readbyqxmd.com/read/28335420/efforts-and-challenges-in-engineering-the-genetic-code
#1
REVIEW
Xiao Lin, Allen Chi Shing Yu, Ting Fung Chan
This year marks the 48th anniversary of Francis Crick's seminal work on the origin of the genetic code, in which he first proposed the "frozen accident" hypothesis to describe evolutionary selection against changes to the genetic code that cause devastating global proteome modification. However, numerous efforts have demonstrated the viability of both natural and artificial genetic code variations. Recent advances in genetic engineering allow the creation of synthetic organisms that incorporate noncanonical, or even unnatural, amino acids into the proteome...
March 14, 2017: Life
https://www.readbyqxmd.com/read/28330604/stable-and-potent-selenomab-drug-conjugates
#2
Xiuling Li, Christopher G Nelson, Rajesh R Nair, Lori Hazlehurst, Tina Moroni, Pablo Martinez-Acedo, Alex R Nanna, David Hymel, Terrence R Burke, Christoph Rader
Selenomabs are engineered monoclonal antibodies with one or more translationally incorporated selenocysteine residues. The unique reactivity of the selenol group of selenocysteine permits site-specific conjugation of drugs. Compared with other natural and unnatural amino acid and carbohydrate residues that have been used for the generation of site-specific antibody-drug conjugates, selenocysteine is particularly reactive, permitting fast, single-step, and efficient reactions under near physiological conditions...
March 9, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28302013/multicyclic-peptides-as-scaffolds-for-the-development-of-tumor-targeting-agents
#3
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/28273378/the-synthesis-of-14-c-4-acetylphenylalanine-effect-on-cell-viability-and-assessment-of-protein-incorporation-in-male-rat-hepatocytes
#4
Brad D Maxwell, Van Ly, Barry Brock, Robert Dodge, Mark Tirmenstein, Jacqueline Calvano
PEGylation is a proven approach to prolonging the duration of action and enhancing biophysical solubility and stability of peptides. 4-Acetylphenylalanine is a novel amino acid with a ketone side chain that is uniquely reactive in proteins. The ketone functionality can react with an amino-oxy functionalized PEG polymer to form a stable oxime adduct of the protein. One concern with using unnatural amino acids, such as 4-acetyl-phenylalanine, is the possibility of it being cleaved from the peptide and becoming incorporated into endogenous proteins...
March 8, 2017: Journal of Labelled Compounds & Radiopharmaceuticals
https://www.readbyqxmd.com/read/28246190/phosphorylation-of-g-protein-coupled-receptors-from-the-barcode-hypothesis-to-the-flute-model
#5
Zhao Yang, Fan Yang, Daolai Zhang, Zhixin Liu, Amy Lin, Chuan Liu, Peng Xiao, Xiao Yu, Jin-Peng Sun
Seven transmembrane G protein-coupled receptors (GPCRs) are often phosphorylated at the C-terminus and on intracellular loops in response to various extracellular stimuli. Phosphorylation of GPCRs by GPCR kinases (GRKs) and certain other kinases can promote the recruitment of arrestin molecules. The arrestins critically regulate GPCR functions, not only by mediating receptor desensitization and internalization, but also by redirecting signalling to G protein-independent pathways via interactions with numerous downstream effector molecules...
February 28, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28230157/highly-sensitive-and-adaptable-fluorescence-quenched-pair-discloses-the-substrate-specificity-profiles-in-diverse-protease-families
#6
Marcin Poreba, Aleksandra Szalek, Wioletta Rut, Paulina Kasperkiewicz, Izabela Rutkowska-Wlodarczyk, Scott J Snipas, Yoshifumi Itoh, Dusan Turk, Boris Turk, Christopher M Overall, Leszek Kaczmarek, Guy S Salvesen, Marcin Drag
Internally quenched fluorescent (IQF) peptide substrates originating from FRET (Förster Resonance Energy Transfer) are powerful tool for examining the activity and specificity of proteases, and a variety of donor/acceptor pairs are extensively used to design individual substrates and combinatorial libraries. We developed a highly sensitive and adaptable donor/acceptor pair that can be used to investigate the substrate specificity of cysteine proteases, serine proteases and metalloproteinases. This novel pair comprises 7-amino-4-carbamoylmethylcoumarin (ACC) as the fluorophore and 2,4-dinitrophenyl-lysine (Lys(DNP)) as the quencher...
February 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28222617/presynaptic-calmodulin-targets-lessons-from-structural-proteomics
#7
Noa Lipstein, Melanie Göth, Christine Piotrowski, Kevin Pagel, Andrea Sinz, Olaf Jahn
Calmodulin (CaM) is a highly conserved Ca(2+)-binding protein that is exceptionally abundant in the brain. In the presynaptic compartment of neurons, CaM transduces changes in Ca(2+) concentration into the regulation of synaptic transmission dynamics. Areas covered: We review selected literature including published CaM interactor screens and outline established and candidate presynaptic CaM targets. We present a workflow of biochemical and structural proteomic methods that were used to identify and characterize the interactions between CaM and Munc13 proteins...
March 2017: Expert Review of Proteomics
https://www.readbyqxmd.com/read/28220771/expanding-the-genetic-code-of-mus-musculus
#8
Songmi Han, Aerin Yang, Soonjang Lee, Han-Woong Lee, Chan Bae Park, Hee-Sung Park
Here we report the expansion of the genetic code of Mus musculus with various unnatural amino acids including N(ɛ)-acetyl-lysine. Stable integration of transgenes encoding an engineered N(ɛ)-acetyl-lysyl-tRNA synthetase (AcKRS)/tRNA(Pyl) pair into the mouse genome enables site-specific incorporation of unnatural amino acids into a target protein in response to the amber codon. We demonstrate temporal and spatial control of protein acetylation in various organs of the transgenic mouse using a recombinant green fluorescent protein (GFPuv) as a model protein...
February 21, 2017: Nature Communications
https://www.readbyqxmd.com/read/28219045/modulating-the-selectivity-of-matriptase-2-inhibitors-with-unnatural-amino-acids
#9
Catherine St-Georges, Antoine Désilets, François Béliveau, Mariana Ghinet, Sébastien P Dion, Éloic Colombo, Pierre-Luc Boudreault, Rafael J Najmanovich, Richard Leduc, Éric Marsault
Matriptase-2, a type II transmembrane serine protease (TTSP), is expressed in the liver and regulates iron homeostasis via the cleavage of hemojuvelin. Matriptase-2 emerges as an attractive target for the treatment of conditions associated with iron overload, such as hemochromatosis or beta-thalassemia. Starting from the crystal structure of its closest homolog matriptase, we constructed a homology model of matriptase-2 in order to further optimize the selectivity of serine trap peptidomimetic inhibitors for matriptase-2 vs matriptase...
March 31, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28213514/peripheral-membrane-interactions-boost-the-engagement-by-an-anti-hiv-1-broadly-neutralizing-antibody
#10
Edurne Rujas, José M M Caaveiro, Sara Insausti, Miguel García-Porras, Kouhei Tsumoto, José L Nieva
The 4E10 antibody displays an extreme breadth of HIV-1 neutralization and therefore constitutes a suitable model system for structure- guided vaccine design and immunotherapeutics against AIDS. In this regard, the relevance of auto- reactivity with membrane lipids for the biological function of this antibody is still a subject of controversy. To address this dispute, herein we have compared the membrane-partitioning ability of the 4E10 antibody and several of its variants, which were mutated at the region of the paratope surface in contact with the membrane-interface...
February 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28213177/tiered-analytics-for-purity-assessment-of-macrocyclic-peptides-in-drug-discovery-analytical-consideration-and-method-development
#11
Jingfang Jenny Qian Cutrone, Xiaohua Stella Huang, Edward S Kozlowski, Ye Bao, Yingzi Wang, Christopher S Poronsky, Dieter M Drexler, Adrienne A Tymiak
Synthetic macrocyclic peptides with natural and unnatural amino acids have gained considerable attention from a number of pharmaceutical/biopharmaceutical companies in recent years as a promising approach to drug discovery, particularly for targets involving protein-protein or protein-peptide interactions. Analytical scientists charged with characterizing these leads face multiple challenges including dealing with a class of complex molecules with the potential for multiple isomers and variable charge states and no established standards for acceptable analytical characterization of materials used in drug discovery...
February 3, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28212794/an-efficient-system-for-incorporation-of-unnatural-amino-acids-in-response-to-the-four-base-codon-agga-in-escherichia-coli
#12
Byeong Sung Lee, Suyeon Kim, Byoung Joon Ko, Tae Hyeon Yoo
BACKGROUND: Adding new amino acids to the set of building blocks for protein synthesis expands the scope of protein engineering, and orthogonal pairs of tRNA and aminoacyl-tRNA synthetase have been developed for incorporating unnatural amino acids (UAAs) into proteins. While diverse systems have been developed to incorporate UAAs in response to the amber codon, less research has been focused on four-base codons despites their advantages. In this study, we report an efficient method to incorporate UAA in response to an AGGA codon in Escherichia coli...
February 14, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28206740/d-amino-acid-levels-in-perfused-mouse-brain-tissue-and-blood-a-comparative-study
#13
Choyce A Weatherly, Siqi Du, Curran Parpia, Polan T Santos, Adam L Hartman, Daniel W Armstrong
The l-enantiomer is the predominant type of amino acid in all living systems. However, d-amino acids, once thought to be "unnatural", have been found to be indigenous even in mammalian systems and increasingly appear to be functioning in essential biological and neurological roles. Both d- and l-amino acid levels in the hippocampus, cortex, and blood samples from NIH Swiss mice are reported. Perfused brain tissues were analyzed for the first time, thereby eliminating artifacts due to endogenous blood, and decreased the mouse-to-mouse variability in amino acid levels...
February 16, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28197734/non-canonical-amino-acids-bearing-thiophene-and-bithiophene-synthesis-by-an-ugi-multicomponent-reaction-and-studies-on-ion-recognition-ability
#14
Cátia I C Esteves, M Manuela M Raposo, Susana P G Costa
Novel thienyl and bithienyl amino acids with different substituents were obtained by a multicomponent Ugi reaction between a heterocyclic aldehyde, an amine, an acid and an isocyanide. Due to the presence of the sulphur heterocycle at the side chain, these unnatural amino acids are highly emissive and bear extra electron donating atoms so they were tested for their ability to act as fluorescent probes and chemosensors in the recognition of biomedically relevant ions in acetonitrile and acetonitrile/water solutions...
February 14, 2017: Amino Acids
https://www.readbyqxmd.com/read/28195736/oxidative-fragmentations-and-skeletal-rearrangements-of-oxindole-derivatives
#15
Hendrik F T Klare, Alexander F G Goldberg, Douglas C Duquette, Brian M Stoltz
An oxidative sequence for the conversion of oxindoles to structurally distinct heterocyclic scaffolds and aniline derivatives is disclosed by the combination of a copper-catalyzed C-H peroxidation and subsequent base-mediated fragmentation reaction. In contrast to classic enzymatic (i.e., kynurenine pathway) and biomimetic methods (i.e., Witkop-Winterfeldt oxidation) for oxidative indole cleavage, this protocol allows for the incorporation of external nucleophiles. The new transformation displays broad functional group tolerance and is applicable to tryptophan derivatives, opening potential new avenues for postsynthetic modification of polypeptides, bioconjugation, and unnatural amino acid synthesis...
February 14, 2017: Organic Letters
https://www.readbyqxmd.com/read/28195700/discovery-and-characterization-of-a-potent-and-specific-peptide-ligand-targeting-endothelial-progenitor-cells-and-endothelial-cells-for-tissue-regeneration
#16
Dake Hao, Wenwu Xiao, Ruiwu Liu, Priyadarsini Kumar, Yuanpei Li, Ping Zhou, Fuzheng Guo, Diana L Farmer, Kit S Lam, Fengshan Wang, Aijun Wang
Endothelial progenitor cells (EPCs) and endothelial cells (ECs) play a vital role in endothelialization and vascularization for tissue regeneration. Various EPC/EC targeting biomolecules have been investigated to improve tissue regeneration with limited success often due to their limited functional specificity and structural stability. One-bead one-compound (OBOC) combinatorial technology is an ultrahigh throughput chemical library synthesis and screening method suitable for ligand discovery against a wide range of biological targets, such as integrins...
March 2, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28192410/an-orthogonalized-platform-for-genetic-code-expansion-in-both-bacteria-and-eukaryotes
#17
James S Italia, Partha Sarathi Addy, Chester J J Wrobel, Lisa A Crawford, Marc J Lajoie, Yunan Zheng, Abhishek Chatterjee
In this study, we demonstrate the feasibility of expanding the genetic code of Escherichia coli using its own tryptophanyl-tRNA synthetase and tRNA (TrpRS-tRNA(Trp)) pair. This was made possible by first functionally replacing this endogenous pair with an E. coli-optimized counterpart from Saccharomyces cerevisiae, and then reintroducing the liberated E. coli TrpRS-tRNA(Trp) pair into the resulting strain as a nonsense suppressor, which was then followed by its directed evolution to genetically encode several new unnatural amino acids (UAAs)...
April 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28191919/lysine-tryptophan-crosslinked-peptides-produced-by-radical-sam-enzymes-in-pathogenic-streptococci
#18
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/28177025/stabilization-of-peptides-against-proteolysis-through-disulfide-bridged-conjugation-with-synthetic-aromatics
#19
Yaqi Chen, Tao Li, Jianguo Li, Shiyan Cheng, Jinghui Wang, Chandra Verma, Yibing Zhao, Chuanliu Wu
Peptides have been promising molecular scaffolds for the development of potential therapeutics with high affinity and specificity to biomacromolecules. However, their inherent proteolytic instability significantly hampers their biological applications. Strategies that can stabilize peptides against proteolytic digestion on the basis of noncovalent interactions-without extensive manipulation of the sequence or use of unnatural residues-are greatly desired. In this work, we developed a general, convenient, and efficient strategy for the stabilization of peptides against proteolysis, which involves noncovalent π-π interactions between aromatic amino acid residues in peptides and synthetic electron-deficient aromatics (NDI), together with the implication of steric hindrance (from the bulky NDI moiety), and the enhancement of peptide α-helicity...
February 8, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28169482/using-diphenylphosphoryl-azide-dppa-for-the-facile-synthesis-of-biodegradable-antiseptic-random-copolypeptides
#20
Yuji Pu, Yu Du, Mya Mya Khin, Vikashini Ravikumar, Scott A Rice, Hongwei Duan, Mary B Chan-Park
A facile method has been developed for the large-scale synthesis of random copolypeptides composed of multiple (i.e., cationic, hydrophobic, and hydrophilic) amino acids and their relative ratios have been optimized for broad-spectrum antibacterial effect. The copolypeptides obtained have measured compositions close to the design ratios in spite of the differing reactivities of the different amino acids. An optimized random copolypeptide of lysine, leucine, and serine (denoted as KLS-3) mimicking the composition of LL-37 host defense peptide gives broad spectrum antibacterial activity against clinically relevant Gram-negative and Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PAO1) with minimum inhibitory concentrations (MICs) of 32-64 μg mL(-1) , as well as good MICs against multidrug resistant Gram-negative bacteria of Escherichia coli EC 958 (64 μg mL(-1) ) and Klebseilla pneumoniae PTR3 (128 μg mL(-1) )...
February 7, 2017: Macromolecular Rapid Communications
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