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Unnatural amino acid

Nikolaos D Georgakopoulos, Sandeep K Talapatra, Jemma Gatliff, Frank Kozielski, Geoff Wells
Non-covalent inhibitors of the Keap1-Nrf2 protein-protein interaction (PPI) have therapeutic potential in a range of disease states including neurodegenerative diseases (Parkinson's and Alzheimer's diseases), chronic obstructive pulmonary disease and various inflammatory conditions. By stalling Keap1-mediated ubiquitination of Nrf2, such compounds can enhance Nrf2 transcriptional activity and activate the expression of a range of genes with antioxidant response elements (AREs) in their promoter regions. Keap1 inhibitors have been identified based on peptide and small molecule templates...
June 21, 2018: Chembiochem: a European Journal of Chemical Biology
Anna-Carin C Carlsson, Matthew R Scholfield, Rhianon Kay Rowe, Melissa Coates Ford, Austin T Alexander, Ryan A Mehl, Pui Shing Ho
The construction of more stable proteins is important in biomolecular engineering, particularly in the design of biologics based therapeutics. We show here that replacing the tyrosine at position 18 (Y18) of T4 lysozyme with the unnatural amino acid meta-chlorotyrosine (mCl Y) increases both the thermal stability (raising the melting temperature by ~1°C and melting enthalpy by 3 kcal/mol) and enzymatic activity at elevated temperatures (15% higher than the parent enzyme at 40°C) of this classic enzyme. The chlorine of mCl Y forms a halogen bond (XB) to the carbonyl oxygen of the peptide bond at glycine 28 (G28) in a tight loop near the active site...
June 19, 2018: Biochemistry
Francesca Micoli, Roberto Adamo, Paolo Costantino
Currently licensed glycoconjugate vaccines are composed of a carbohydrate moiety covalently linked to a protein carrier. Polysaccharides are T-cell independent antigens able to directly stimulate B cells to produce antibodies. Disease burden caused by polysaccharide-encapsulated bacteria is highest in the first year of life, where plain polysaccharides are not generally immunogenic, limiting their use as vaccines. This limitation has been overcome by covalent coupling carbohydrate antigens to proteins that provide T cell epitopes...
June 15, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Pravin C Patil, Frederick A Luzzio
A novel tert -butyl 2-(1-oxoisolndolin-2-yl)acetate derivative is selectively alkylated with propargyl bromide in the presence of lithium hexamethyldisilazide. After removal of the tert -butyl protecting group, the resulting N -isoindolinyl (ethynylalanine) derivative is reacted with a series of azides under 'click conditions'. The click reactions afford an array of N -isoindolinyl-1,2,3-triazolylalanine derivatives as the free carboxylic adds. Following esterification, the N -isoindolinone protecting group is then transformed into the more easily removable phthaloyl group by selective oxidation at the benzylic position...
September 2017: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry
Lei Jin, Shuai Zhao, Xin Chen
A practical synthesis of both enantiomers of unnatural phenylalanine derivatives by using two pseudoenantiomeric phase transfer catalysts is described. Through asymmetric α-alkylation of glycine Schiff base with substituted benzyl bromides and 1-(bromomethyl)naphthalene under the catalysis of O -allyl- N -(9-anthracenmethyl) cinchoninium bromide ( 1f ) and O -allyl- N -(9-anthracenylmethyl)cinchonidium bromide ( 1i ), respectively, a series of both ( R )- and ( S )-enantiomers of unnatural α-amino acid derivatives were obtained in excellent yields and enantioselectivity...
June 12, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Rosario Oliva, Marco Chino, Katia Pane, Valeria Pistorio, Augusta De Santis, Elio Pizzo, Gerardino D'Errico, Vincenzo Pavone, Angela Lombardi, Pompea Del Vecchio, Eugenio Notomista, Flavia Nastri, Luigi Petraccone
Cationic antimicrobial peptides (CAMPs) are a promising alternative to treat multidrug-resistant bacteria, which have developed resistance to all the commonly used antimicrobial, and therefore represent a serious threat to human health. One of the major drawbacks of CAMPs is their sensitivity to proteases, which drastically limits their half-life. Here we describe the design and synthesis of three nine-residue CAMPs, which showed high stability in serum and broad spectrum antimicrobial activity. As for all peptides a very low selectivity between bacterial and eukaryotic cells was observed, we performed a detailed biophysical characterization of the interaction of one of these peptides with liposomes mimicking bacterial and eukaryotic membranes...
June 11, 2018: Scientific Reports
Alaa F Nahhas, Run Chang, Thomas J Webster
Hydrogelators are crosslinked polymeric networks that are capable of holding large amounts of water by surface tension. High-water absorption capacity makes hydrogels readily biocompatible and, thus, more attractive for medical applications. The objective of the present in vitro study was to test supramolecular hydrogelators for multiple biomedical applications: bacterial- and cancer-related diseases. Four naphthalene-tripeptides and their D-enantiomers were synthesized using an Fmoc Solid Phase Peptide Synthesis strategy and were tested for their activity on normal and cancer cells as well as bacteria...
May 1, 2018: Journal of Biomedical Nanotechnology
François Bédard, Eric Biron
A wide variety of antimicrobial peptides produced by lactic acid bacteria (LAB) have been identified and studied in the last decades. Known as bacteriocins, these ribosomally synthesized peptides inhibit the growth of a wide range of bacterial species through numerous mechanisms and show a great variety of spectrum of activity. With their great potential as antimicrobial additives and alternatives to traditional antibiotics in food preservation and handling, animal production and in veterinary and medical medicine, the demand for bacteriocins is rapidly increasing...
2018: Frontiers in Microbiology
Adarshi Welegedara, Luke A Adams, Bim Graham, Thomas Huber, Gottfried Otting
Selenocysteine (Sec) is a naturally occurring amino acid that is also referred to as the 21st amino acid. Site-specific incorporation of Sec into proteins is attractive, because the reactivity of a selenol group exceeds that of a thiol group and thus allows site-specific protein modifications. It is incorporated into proteins by an unusual enzymatic mechanism which, in E. coli and other organisms, involves the recognition of a selenocysteine insertion sequence (SECIS) in the mRNA of the target protein. Reengineering of the natural machinery for Sec incorporation at arbitrary sites independent of SECIS elements, however, is challenging...
June 6, 2018: Bioconjugate Chemistry
Xiaobao Bi, Juan Yin, Xinya Hemu, Chang Rao, James P Tam, Chuan-Fa Liu
Backbone-cyclic proteins are of great scientific and therapeutic interest owing to their higher stability over their linear counterparts. Modification of such cyclic proteins at selected site would further enhance their versatility. Here we report a chemoenzymatic strategy to engineer site-selectively modified cyclic proteins by combining butelase-mediated macrocyclization with the genetic code expansion methodology. Using this strategy, we prepared a cyclic protein which was modified with biotin or a cell-penetrating peptide at a genetically incorporated non-canonical amino acid, making the cyclization-stabilized protein further amenable for site-specific immobilization and intracellular delivery...
June 5, 2018: Bioconjugate Chemistry
Andrej Babic, Laurent Vinet, Vineetha Chellakudam, Karolina Janikowska, Eric Allemann, Norbert Lange
Novel drug delivery systems targeting native, transplanted or cancerous beta-cells are of utmost importance. Herein, we present new exendin-4 derivatives with modified unnatural amino acids at strategic positions within the polypeptide sequence. The modified peptides allowed modular orthogonal chemical modifications to attach imaging agents and amphiphilic squalene-PEG groups. The resulting conjugates, SQ-PEG-ExC1-Cy5 and SQ-PEG-ExC40-Cy5 fluorescence probes display low nM affinity to GLP-1R in fluorescence-based binding assays with EC50 at 1...
June 5, 2018: Bioconjugate Chemistry
Takafumi Tanaka, Tsukushi Tanaka, Taro Tsuji, Ryo Yazaki, Takashi Ohshima
A new strategy, a transient homocoupling dimer strategy, for direct catalytic oxidative cross-enolate coupling reactions is developed. Cross-enolate coupling products bearing a (contiguous) tetrasubstituted carbon center were obtained chemoselectively without the need for stoichiometric amounts of strong bases/metal oxidants, and thus, the present catalysis provides a general method for the synthesis of unnatural α,α-disubstituted amino acid motifs. The distinct transformation of azlactone and 2-acylimidazole units highlighted the synthetic utility of the present catalysis...
May 31, 2018: Organic Letters
Suresh S Pujari, Yi Zhang, Shaofei Ji, Mark D Distefano, Natalia Y Tretyakova
DNA-protein cross-links (DPCs) are super-bulky DNA adducts induced by common chemotherapeutic agents, reactive oxygen species, and aldehydes, and also formed endogenously as part of epigenetic regulation. Despite their presence in most cells and tissues, the biological effects of DPCs are poorly understood due to the difficulty of constructing site-specific DNA-protein conjugates. In the present work, a new approach of conjugating proteins to DNA using oxime ligation was used to generate model DPCs structurally analogous to lesions formed in cells...
May 31, 2018: Chemical Communications: Chem Comm
Zhenling Cui, Yue Wu, Sergey Mureev, Kirill Alexandrov
Sense codon reassignment to unnatural amino acids (uAAs) represents a powerful approach for introducing novel properties into polypeptides. The main obstacle to this approach is competition between the native isoacceptor tRNA(s) and orthogonal tRNA(s) for the reassigned codon. While several chromatographic and enzymatic procedures for selective deactivation of tRNA isoacceptors in cell-free translation systems exist, they are complex and not scalable. We designed a set of tRNA antisense oligonucleotides composed of either deoxy-, ribo- or 2'-O-methyl ribonucleotides and tested their ability to efficiently complex tRNAs of choice...
May 28, 2018: Nucleic Acids Research
Triveena M Ramsis, Shereen E Abdel Karim, Niki Vassilaki, Efseveia Frakolaki, Ahmed A M Kamal, Grigoris Zoidis, Nermin S Ahmed, Ashraf H Abadi
Here we report a series of potent anti-HCV agents bearing a symmetrical benzidine l-prolinamide backbone with different capping groups including alkyl/aryl carbamates of natural and unnatural valine and leucine amino acids. All compounds were investigated for their inhibitory activity in an HCV replicon assay on genotype 1b. The novel compounds share some chemical and clinical attributes of commercially available NS5A inhibitors. Compounds 5 and 6 with unnatural capping residue and ethyl and isobutyl carbamates showed EC50 values in the picomolar range with a low toxicity profile and selectivity indices of several orders of magnitude...
May 25, 2018: Archiv der Pharmazie
Yan Chen, Yanmin Wan, Nanxi Wang, Zhe Yuan, Wei Niu, Qingsheng Li, Jiantao Guo
Large efforts have been devoted to the genetic code engineering in the past decade, aiming for unnatural amino acid mutagenesis. Recently, an increasing number of studies were reported to employ quadruplet codons to encode unnatural amino acids. We and others have demonstrated that the quadruplet decoding efficiency could be significantly enhanced by an extensive engineering of tRNAs bearing an extra nucleotide in their anticodon loops. In this work, we report the identification of tRNA mutants derived from directed evolution to efficiently decode a UAGA quadruplet codon in mammalian cells...
May 22, 2018: ACS Synthetic Biology
Aleksandar Todorovic, Cody J Lensing, Jerry Ryan Holder, Joseph W Scott, Nicholas B Sorensen, Carrie Haskell-Luevano
The melanocortin system regulates an array of diverse physiological functions including pigmentation, feeding behavior, energy homeostasis, cardiovascular regulation, sexual function, and steroidogenesis. Endogenous melanocortin agonist ligands all possess the minimal messaging tetrapeptide sequence His-Phe-Arg-Trp. Based on this endogenous sequence, the Ac-His1-DPhe2-Arg3-Trp4-NH2 tetrapeptide has previously been shown to be a useful scaffold when utilizing traditional positional scanning approaches to modify activity at the various melanocortin receptors (MC1-5R)...
May 21, 2018: ACS Chemical Neuroscience
Caroline Kearney, Lukasz T Olenginski, Trexler D Hirn, Gwendolyn D Fowler, Daniyal Tariq, Scott H Brewer, Christine M Phillips-Piro
The vibrational reporter unnatural amino acid (UAA) 4-cyano-l-phenylalanine (pCNF) was genetically incorporated individually at three sites (5, 36, and 78) in the heme protein Caldanaerobacter subterraneus H-NOX to probe local hydration environments. The UAA pCNF was incorporated site-specifically using an engineered, orthogonal tRNA synthetase in E. coli . The ability of all of the pCNF-containing H-NOX proteins to form the ferrous CO, NO, or O2 ligated and unligated states was confirmed with UV-Vis spectroscopy...
April 9, 2018: RSC Advances
Yifan Wang, Wendell P Griffith, Jiasong Li, Teruaki Koto, Daniel J Wherritt, Elizabe Fritz, Aimin Liu
Cysteamine dioxygenase (ADO) is a thiol dioxygenase whose study has been stagnated by ambiguity as to whether or not it possesses an anticipated protein-derived cofactor. Herein, we report the discovery and elucidation of a Cys-Tyr cofactor in human ADO, crosslinked between Cys220 and Tyr222 through a thioether (C-S) bond. By genetically incorporating an unnatural amino acid 3,5-difluoro-tyrosine (F2-Tyr) specifically into Tyr222 of human ADO, we identified an autocatalytic oxidative carbon-fluorine bond activation and fluoride release by mass spectrometry and 19F NMR spectroscopy...
May 11, 2018: Angewandte Chemie
Elizabeth R Cleverdon, Tasha R Davis, James L Hougland
Ghrelin is a small peptide hormone that undergoes a unique posttranslational modification, serine octanoylation, to play its physiological roles in processes including hunger signaling and glucose metabolism. Ghrelin O-acyltransferase (GOAT) catalyzes this posttranslational modification, which is essential for ghrelin to bind and activate its cognate GHS-R1a receptor. Inhibition of GOAT offers a potential avenue for modulating ghrelin signaling for therapeutic effect. Defining the molecular characteristics of ghrelin that lead to binding and recognition by GOAT will facilitate the development and optimization of GOAT inhibitors...
April 21, 2018: Bioorganic Chemistry
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