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Unnatural amino acid

Diana Wesselinova, Emilia D Naydenova, S Staykova, I G Goshev, L Vezenkov
BACKGROUND: Based on the structure of RC-121 (D-Phe-c (Cys-Tyr-D-Trp-Lys-Val-Cys)-Thr-NH2, - synthetic derivatives of somatostatin), some analogs were synthesized and tested for in vitro cytotoxic and antioxidant activity. OBJECTIVES: The new analogs were modifyed at position 5 with Dap (diaminopropanoic acid), Dab (diaminobutanoic acid) and Orn and at position 6 with the unnatural amino acids Tle (t-leucine). METHODS: The in vitro cytotoxic effects of the substances were investigated against a panel of human tumor cell lines HT-29 (human colorectal cancer cell line), MDA-MB-23 (human breast cancer cell line), Hep G-2 (human hepatocellular carcinoma cell line) and HeLa (cervical cancer cell line)...
April 17, 2018: Anti-cancer Agents in Medicinal Chemistry
Tuanwei Li, Le Liu, Titao Jing, Zheng Ruan, Pan Yuan, Lifeng Yan
Photobleaching and bio-toxicity are the main bottlenecks for organic fluorescent dyes applied in real-time dynamic monitoring of living cells. Here, an unnatural amino acid (UAA), 4-nitro-3-phenyl-L-alanine (NPA), was used as a scaffold to covalently link a near infrared (NIR) fluorophore Cy5.5, and an amphiphilic polypeptide Poly[oligo(ethylene glycol) methyl ether methacrylate]-block-poly[2-Amino-N4-(2-diisopropylamino-ethyl)-L-Aspartic acid] (P(OEGMA)21-P(Asp)16-iPr) was then conjugated for increasing the photostability and improving the biocompatibility simultaneously...
April 13, 2018: ACS Applied Materials & Interfaces
Viktoria Klippenstein, Laetitia Mony, Pierre Paoletti
Approaches to remotely control and monitor ion channel operation with light are expanding rapidly in the biophysics and neuroscience fields. A recent development directly introduces light sensitivity into proteins by utilizing photosensitive unnatural amino acids (UAAs) incorporated using the genetic code expansion technique. The introduction of UAAs results in unique molecular level control and, when combined with the maximal spatiotemporal resolution and poor invasiveness of light, enables direct manipulation and interrogation of ion channel functionality...
April 10, 2018: Trends in Biochemical Sciences
Partha Sarathi Addy, James S Italia, Abhishek Chatterjee
Approaches enabling chemoselective covalent modification of proteins in a site-specific manner has emerged as a powerful technology for a wide range of applications. The electron-reach unnatural amino acid 5-hydroxytryptophan was recently genetically encoded in both E. coli and eukaryotes, allowing its site-specific incorporation into virtually any recombinant protein. Here we report the chemoselective conjugation of various aromatic amines to full-length proteins under mild oxidative conditions targeting the site-specifically incorporated 5-hydroxytryptophan residue...
April 12, 2018: Chembiochem: a European Journal of Chemical Biology
R A Aycock, D B Vogt, N T Jui
A robust system for the preparation of β-heteroaryl α-amino acid derivatives has been developed using photoredox catalysis. This system operates via regiospecific activation of halogenated pyridines (or other heterocycles) and conjugate addition to dehydroalanine derivatives to deliver a wide range of unnatural amino acids. This process was conducted with good efficiency on large scale, the application of these conditions to amino ketone synthesis is shown, and a simple protocol is given for the preparation of enantioenriched amino acid synthesis, from a number of radical precursors...
December 1, 2017: Chemical Science
Feng Li, Huan Li, Qian Zhai, Fuyang Li, Tailin Wu, Xin Sha, Bobo Zhang, Weizhou Yang, Zifan Lu, Huiren Tao
Bone homeostasis is maintained by a dynamic balance between osteoblastic bone formation and osteoclastic bone resorption. The receptor activator of nuclear-κB ligand (RANKL) is essential for the function of the bone-resorbing osteoclasts, and targeting RANKL has been proved highly successful in osteoporosis patients. This study aimed to design a novel vaccine targeting RANKL and evaluate its therapeutic effects in OVX-induced bone loss model. Anti-RANKL vaccine was generated by incorporating the unnatural amino acid p-nitrophenylalanine (pNO2 Phe) into selected sites in the murine RANKL (mRANKL) molecule...
March 28, 2018: Biochemical and Biophysical Research Communications
Nanxi Wang, Bing Yang, Caiyun Fu, He Zhu, Feng Zheng, Tomonori Kobayashi, Jun Liu, Shanshan Li, Cheng Ma, Peng George Wang, Qian Wang, Lei Wang
Introducing new chemical reactivity into proteins in living cells would endow innovative covalent bonding ability to proteins for research and engineering in vivo. Latent bioreactive unnatural amino acids (Uaas) can be incorporated into proteins to react with target natural amino acid residues via proximity-enabled reactivity. To expand the diversity of proteins amenable to such reactivity in vivo, a chemical functionality that is biocompatible and able to react with multiple natural residues under physiologi-cal conditions is highly desirable...
March 30, 2018: Journal of the American Chemical Society
Subhendu Sekhar Bag, Suranjan De
The solvatochromic IR responsivity of small side chain -NCS in two unexplored unnatural amino acids, isothiocyanyl alanine (NCS Ala = Ita) and lysine (NCS Lys = Itl), without perturbing the conformation is demonstrated in two designed short tripeptide (BocAla-NCS Ala-Ala-OMe) and hexapeptide (BocLeu-Val-Phe-Phe-NCS Lys-Gly-OMe). Demonstration of site specific fluorescent labeling in both the peptides and ligation type reaction inNCS Lys indicates the novelty of these two amino acids as alternative to the available canonical amino acids...
February 12, 2018: Bioorganic & Medicinal Chemistry Letters
Li Chen, Nathchar Naowarojna, Heng Song, Shu Wang, Jianyun Wang, Zixin Deng, Changming Zhao, Pinghua Liu
Ovothiol is a histidine thiol derivative. The biosynthesis of ovothiol involves an extremely efficient trans-sulfuration strategy. The non-heme iron enzyme OvoA catalyzed oxidative coupling be-tween cysteine and histidine is one of the key steps. Besides catalyzing the oxidative coupling between cysteine and histidine, OvoA also catalyzes the oxi-dation of cysteine to cysteine sulfinic acid (cysteine dioxygenase activity). Thus far, very little mecha-nistic information is available for OvoA-catalysis. In this report, we measured the kinetic isotope effect (KIE) in OvoA-catalysis using the isotopically sensitive branching method...
March 15, 2018: Journal of the American Chemical Society
Hua Lin, Jonathan Z Long, Alexander M Roche, Katrin J Svensson, Florence Dou, Mi Ra Chang, Timothy Strutzenberg, Claudia Ruiz, Michael D Cameron, Scott J Novick, Charles M Berdan, Sharon Louie, Daniel K Nomura, Bruce M Spiegelman, Patrick R Griffin, Theodore M Kamenecka
N-acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. We found that administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure indicating that this pathway might be useful for treating obesity and associated disorders. We report the full account of the synthesis and mitochondrial uncoupling bioactivity of lipidated N-acyl amino acids and their unnatural analogs. Unsaturated fatty acid chains of medium length and neutral amino acid head groups are required for optimal uncoupling activity on mammalian cells...
March 13, 2018: Journal of Medicinal Chemistry
Tom H Wright, Benjamin G Davis
Methods for installing natural and unnatural amino acids and their modifications into proteins in a benign and precise manner are highly sought-after in protein science. Here we describe a protocol for 'post-translational mutagenesis' that enables the programmed installation of protein side chains through the use of rapid, mild and operationally simple free-radical chemistry performed on recombinantly expressed and purified proteins. By introduction of protein dehydroalanine (Dha) residues (in this instance, from a unique cysteine residue introduced by site-directed mutagenesis) as free-radical trapping 'tags' for downstream modification, exquisite control over the site of subsequent modification is achieved...
October 2017: Nature Protocols
Élie Besserer-Offroy, Patrick Bérubé, Jérôme Côté, Alexandre Murza, Jean-Michel Longpré, Robert Dumaine, Olivier Lesur, Mannix Auger-Messier, Richard Leduc, Éric Marsault, Philippe Sarret
The apelinergic system is an important player in the regulation of both vascular tone and cardiovascular function, making this physiological system an attractive target for drug development for hypertension, heart failure and ischemic heart disease. Indeed, apelin exerts a positive inotropic effect in humans whilst reducing peripheral vascular resistance. In this study, we investigated the signaling pathways through which apelin exerts its hypotensive action. We synthesized a series of apelin-13 analogs whereby the C-terminal Phe13 residue was replaced by natural or unnatural amino acids...
March 9, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Philip A Cistrone, Anthony P Silvestri, Jordi C J Hintzen, Philip E Dawson
Peptide macrocycles are widely utilized in the development of high affinity ligands including stapled α-helices. The linear rigidity of a 1,3-diynyl linkage provides an optimal distance (7 Å) between β- carbons of the i, i+4 amino acid side chains, suggesting its utility in stabilizing α-helical structures. Here we report the development of an on-resin strategy for an intramolecular Glaser reaction between two alkyne-terminated side chains using copper chloride, an essential bpy-diol ligand, and diisopropylethylamine, at room temperature...
March 7, 2018: Chembiochem: a European Journal of Chemical Biology
Charlène Gadais, Emmanuelle Devillers, Vincent Gasparik, Evelyne Chelain, Julien Pytkowicz, Thierry Brigaud
In order to accurately probe the local hydrophobicity increase of peptide sequences by trifluoromethylated amino acids (TfmAAs) incorporation, the chromatographic hydrophobicity indexes (φ0) of three series of tripeptides containing three unnatural trifluoromethylated amino acids have been measured and compared to the indexes of their non-fluorinated analogs. The hydrophobic contribution of each fluorinated amino acids was quantified by varying the position and the protection of (R) and (S)-α-trifluoromethyl alanine (TfmAla), (S)-trifluoromethyl cysteine (TfmCys) and (L)-trifluoromethionine (TFM) in a short peptide sequence...
March 7, 2018: Chembiochem: a European Journal of Chemical Biology
Farhan Abu, Justin G Wang, Yangkyun Oh, Jingjing Deng, Thomas A Neubert, Greg S B Suh
Sweet-insensitive Drosophila mutants are unable to readily identify sugar. In presence of wild-type (WT) flies, however, these mutant flies demonstrated a marked increase in their preference for nutritive sugar. Real-time recordings of starved WT flies revealed that these flies discharge a drop from their gut end after consuming nutritive sugars, but not nonnutritive sugars. We proposed that the drop may contain a molecule(s) named calorie-induced secreted factor (CIF), which serves as a signal to inform other flies about its nutritional value...
March 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Marco Sabatini, Valerija Karaluka, Rachel Lanigan, Lee Boulton, Matthew Badland, Tom David Sheppard
The amidation of unprotected amino acids has been investigated using a variety of 'classical' coupling reagents, and stoichiometric or catalytic group(IV) metal salts and boron Lewis acids. The scope of the reaction was explored through the attempted synthesis of amides derived from twenty natural, and several unnatural, amino acids, as well as a wide selection of primary and secondary amines. The study also examines the synthesis of medicinally relevant compounds, and the scalability of this direct amidation approach...
March 5, 2018: Chemistry: a European Journal
Fanjie Meng, Mathias M J Bellaiche, Jae-Yeol Kim, Gül H Zerze, Robert B Best, Hoi Sung Chung
Monomers of amyloid-β (Aβ) protein are known to be disordered, but there is considerable controversy over the existence of residual or transient conformations that can potentially promote oligomerization and fibril formation. We employed single-molecule Förster resonance energy transfer (FRET) spectroscopy with site-specific dye labeling using an unnatural amino acid and molecular dynamics simulations to investigate conformations and dynamics of Aβ isoforms with 40 (Aβ40) and 42 residues (Aβ42). The FRET efficiency distributions of both proteins measured in phosphate-buffered saline at room temperature show a single peak with very similar FRET efficiencies, indicating there is apparently only one state...
February 27, 2018: Biophysical Journal
Dhruva Katrekar, Ana M Moreno, Genghao Chen, Atharv Worlikar, Prashant Mali
Recombinant adeno-associated viruses (AAVs) are among the most commonly used vehicles for in vivo gene delivery. However, their tropism is limited, and additionally their efficacy can be negatively affected by prevalence of neutralizing antibodies in sera. Methodologies to systematically engineer AAV capsid properties would thus be of great relevance. In this regard, we develop here multi-functional AAVs by engineering precision tethering of oligonucleotides onto the AAV surface, and thereby enabling a spectrum of nucleic-acid programmable functionalities...
February 26, 2018: Scientific Reports
Zhigang Lyu, Lei Kang, Zakey Yusuf Buuh, Dawei Jiang, Jeffrey C McGuth, Juanjuan Du, Haley L Wissler, Weibo Cai, Rongsheng E Wang
Genetic incorporation of unnatural amino acids (UAAs) provides a unique approach to the synthesis of site-specific antibody conjugates that are homogeneous and better defined constructs than random conjugates. Yet, the yield varies for every antibody, and the process is costly and time-consuming. We have developed a switchable αGCN4-Fab conjugate that incorporates UAA p-acetylphenylalanine. The GCN4 peptide is used as a switch, and antibodies fused by GCN4 can direct the αGCN4-Fab conjugate to target different cancer cells for diagnosis, imaging, or therapeutic treatment...
February 28, 2018: ACS Chemical Biology
Carolina Prolo, Natalia Rios, Lucia Piacenza, María Noel Álvarez, Rafael Radi
In the last two decades, there has been a significant advance in understanding the biochemistry of peroxynitrite, an endogenously-produced oxidant and nucleophile. Its relevance as a mediator in several pathologic states and the aging process together with its transient character and low steady-state concentration, motivated the development of a variety of techniques for its unambiguous detection and estimation. Among these, fluorescence and chemiluminescence approaches have represented important tools with enhanced sensitivity but usual limited specificity...
February 15, 2018: Free Radical Biology & Medicine
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