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Unnatural amino acid

Marshall S Padilla, Christopher A Farley, Lindsay E Chatkewitz, Douglas D Young
Reversing a bioconjugation in a spatial and temporal fashion has widespread applications, especially toward targeted drug delivery. We report the synthesis and incorporation of an unnatural amino acid with an alkyne modified dimethoxy-ortho-nitrobenzyl caging group. This unnatural amino acid can be utilized in a Glaser-Hay conjugation to generate a bioconjugate, but also is able to disrupt the bioconjugate when irradiated with light. These combined features allow for the preparation of bioconjugates with a high degree of site-specificity and allow for the separation of the two components if necessary...
October 19, 2016: Tetrahedron Letters
Wei Kang, Hanhan Liu, Lingman Ma, Mengxiao Wang, Shanshan Wei, Pengbo Sun, Meiling Jiang, Min Guo, Changlin Zhou, Jie Dou
Broad spectrum activities, a unique mode of actions and rare resistant variants make antimicrobial peptide (AMP) a potential alternative to antibiotics. However, AMPs still have limitations in clinical development due to their physiological stability, toxicity and manufacturing costs. Cbf-14, derived from cathelicidin-BF has been proven to be effective against drug-resistant bacteria. Herein, a series of Cbf-14 mutants were designed to overcome these limitations. Design strategies included substitutions of lysine (Lys) or leucine (Leu) with similar residues such as ornithine (Orn) and norleucine (Ile), which are unnatural amino acids, to generate AMPs with enhanced therapeutic potential...
May 15, 2017: European Journal of Pharmaceutical Sciences
K W Swiderska, A Szlachcic, A Czyrek, M Zakrzewska, J Otlewski
Recent advances in site-specific protein modification include the increasingly popular incorporation of unnatural amino acid(s) using amber codon, a method developed by Schultz and coworkers. In this study, we employ this technique to introduce propargyllysine (PrK) in human fibroblast growth factor 2 (FGF2). Owing to an alkyne moiety in its side chain, PrK is compatible with Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC). We successfully tested CuAAC-mediated conjugation of FGF2 with two compounds - a fluorophore carboxyrhodamine 110 or a cytotoxic drug monomethyl auristatin E (MMAE)...
May 5, 2017: Bioorganic & Medicinal Chemistry
Dominik Schumacher, Oliver Lemke, Jonas Helma, Lena Gerszonowicz, Verena Waller, Tina Stoschek, Patrick M Durkin, Nediljko Budisa, Heinrich Leonhardt, Bettina G Keller, Christian P R Hackenberger
The broad substrate tolerance of tubulin tyrosine ligase is the basic rationale behind its wide applicability for chemoenzymatic protein functionalization. In this context, we report that the wild-type enzyme enables ligation of various unnatural amino acids that are substantially bigger than and structurally unrelated to the natural substrate, tyrosine, without the need for extensive protein engineering. This unusual substrate flexibility is due to the fact that the enzyme's catalytic pocket forms an extended cavity during ligation, as confirmed by docking experiments and all-atom molecular dynamics simulations...
May 1, 2017: Chemical Science
Timothy Lynagh, Emelie Flood, Céline Boiteux, Matthias Wulf, Vitaly V Komnatnyy, Janne M Colding, Toby W Allen, Stephan A Pless
Increased extracellular proton concentrations during neurotransmission are converted to excitatory sodium influx by acid-sensing ion channels (ASICs). 10-fold sodium/potassium selectivity in ASICs has long been attributed to a central constriction in the channel pore, but experimental verification is lacking due to the sensitivity of this structure to conventional manipulations. Here, we explored the basis for ion selectivity by incorporating unnatural amino acids into the channel, engineering channel stoichiometry and performing free energy simulations...
May 12, 2017: ELife
Steven Y Reece, Mohammad R Seyedsayamdost
Escherichia coli class Ia ribonucleotide reductase (RNR) catalyzes the conversion of nucleotides to 2'-deoxynucleotides using a radical mechanism. Each turnover requires radical transfer from an assembled diferric tyrosyl radical (Y•) cofactor to the enzyme active site over 35 Å away. This unprecedented reaction occurs via an amino acid radical hopping pathway spanning two protein subunits. To study the mechanism of radical transport in RNR, a suite of biochemical approaches have been developed, such as site-directed incorporation of unnatural amino acids with altered electronic properties and photochemical generation of radical intermediates...
May 9, 2017: Essays in Biochemistry
Kousuke Tsuchiya, Keiji Numata
Polypeptides containing 2-aminoisobutyric acid (Aib) units as an unnatural amino acid residue were synthesized by papain-catalyzed chemoenzymatic polymerization of a tripeptide ethyl ester l-Ala-Aib-l-Ala-OEt in an aqueous medium. The Aib-containing polypeptide adopted an α-helix conformation in both the solid and solution phases, which was induced by the periodic Aib residue.
May 9, 2017: Chemical Communications: Chem Comm
Stephanie A Fisher, Alexander E G Baker, Molly S Shoichet
Hydrogels are used in a wide variety of biomedical applications including tissue engineering, biomolecule delivery, cell delivery, and cell culture. These hydrogels are often designed with a specific biological function in mind, requiring the chemical incorporation of bioactive factors to either mimic extracellular matrix or to deliver a payload to diseased tissue. Appropriate synthetic techniques to ligate bioactive factors, such as peptides and proteins, onto hydrogels are critical in designing materials with biological function...
May 8, 2017: Journal of the American Chemical Society
Peng Teng, Ning Ma, Darrell Cole Cerrato, Fengyu She, Timothy Odom, Xing Wang, Li-June Ming, Arjan van der Vaart, Lukasz Wojtas, Hai Xu, Jianfeng Cai
New types of foldamer scaffolds are formidably challenging to design and synthesize yet highly desirable as structural mimics of peptides/proteins with a wide repertoire of functions. In particular, the development of peptidomimetic helical foldamers holds promise for new biomaterials, catalysts and drug molecules. Unnatural L-sulfono-γ-AApeptides were recently developed and shown to have potential applications in both biomedical and material sciences. However, D-sulfono-γ-AApeptides, the enantiomers of L-sulfono-γ-AApeptides, have never been studied due to the lack of high resolution three-dimensional structures to guide structure-based design...
May 8, 2017: Journal of the American Chemical Society
Philip J M Johnson, Klemens L Koziol, Peter Hamm
Azidohomoalanine (Aha) is an unnatural amino acid containing an infrared active azido side chain group that can, through frequency shifts of the azido stretch vibration, act as a probe of local structure. To realize the potential of such structural probes for protein science, we have developed a two-dimensional infrared spectrometer employing fast mechanical scanning and intrinsic phasing of the resulting spectra, leading to a lower sensitivity limit of ∼100 μOD level samples. Using this approach, we quantify the biomolecular recognition between a PDZ2 domain and two Aha-mutated peptides...
May 8, 2017: Journal of Physical Chemistry Letters
Charles A Galea, Meiling Han, Yan Zhu, Kade Roberts, Jiping Wang, Philip E Thompson, Jian L, Tony Velkov
The increasing prevalence of polymyxin-resistant bacteria has stimulated the search for improved polymyxin lipopeptides. Here we describe the sequence and product profile for polymyxin D nonribosomal peptide synthetase from Paenibacillus polymyxa ATCC 10401. The polymyxin D synthase gene cluster comprised five genes that encoded ABC transporters (pmxC and pmxD) and enzymes responsible for the biosynthesis of polymyxin D (pmxA, pmxB, and pmxE). Unlike polymyxins B and E, polymyxin D contains d-Ser at position 3 as opposed to l-α,γ-diaminobutyric acid and has an l-Thr at position 7 rather than l-Leu...
May 2, 2017: Journal of Natural Products
Smriti Rekha Deka, Santosh Yadav, Dheeresh Kumar, Sumit Garg, Manohar Mahato, Ashwani Kumar Sharma
In the recent studies, it has been demonstrated that incorporation of unnatural amino acid, α,β-dehydrophenylalanine, in small peptides results in stable self-assembled nanostructures with different sizes and shapes. Here, we have replaced the natural amino acid, phenylalanine, from our earlier reported work on self-assembled peptide, Boc-Pro-Phe-Gly-OMe, with a constrained dehydro amino acid, α,β-dehydrophenylalanine, to study its influence on self-assembled nanostructures. Dehydrotripeptide, Boc-Pro-ΔPhe-Gly-OMe, self-assembled into nanostructures in aqueous solutions and formed hydrophobic matrix with improved encapsulation efficiency of hydrophobic molecules...
April 20, 2017: Colloids and Surfaces. B, Biointerfaces
Milata M Abraham, Ryan E Denton, Richard W Harper, William L Scott, Martin J O'Donnell, Jacob D Durrant
Virtual molecular catalogs have limited utility if member compounds are (1) difficult to synthesize or (2) unlikely to have biological activity. The Distributed Drug Discovery (D3) program addresses the synthesis challenge by providing scientists with a free virtual D3 catalog of 73,024 easy-to-synthesize N-acyl unnatural α-amino acids, their methyl esters, and primary amides. The remaining challenge is to document and exploit the bioactivity potential of these compounds. In the current work, a search process is described that retrospectively identifies all virtual D3 compounds classified as bioactive hits in PubChem-cataloged experimental assays...
April 28, 2017: Chemical Biology & Drug Design
Hader E Elashal, Yonnette E Sim, Monika Raj
Fmoc solid phase peptide synthesis of thioesters for the chemical synthesis of proteins via native chemical ligation is a challenge. We have developed a versatile approach for direct synthesis of peptide thioesters from a solid support utilizing Fmoc chemistry. Peptide thioester synthesis is performed by the formation of a cyclic urethane moiety via a selective reaction of the backbone amide chain with the side group of serine. The activated cyclic urethane moiety undergoes displacement by a thiol to generate the thioester directly from the solid support...
January 1, 2017: Chemical Science
Yun Ge, Xinyuan Fan, Peng R Chen
The genetic code expansion strategy allowed incorporation of unnatural amino acids (UAAs) bearing diverse functional groups into proteins, providing a powerful toolkit for protein manipulation in living cells. We report a multifunctional UAA, N(ε)-p-azidobenzyloxycarbonyl lysine (PABK), that possesses a panel of unique properties capable of fulfilling various protein manipulation purposes. In addition to being used as a bioorthogonal ligation handle, an infrared probe and a photo-affinity reagent, PABK was shown to be chemically decaged by trans-cyclooctenols via a strain-promoted 1,3-dipolar cycloaddition, which provides a new bioorthogonal cleavage strategy for intracellular protein activation...
December 1, 2016: Chemical Science
Andreas Evers, Torsten Haack, Martin Lorenz, Martin Bossart, Ralf Elvert, Bernd Henkel, Siegfried Stengelin, Michael Kurz, Maike Glien, Angela Dudda, Katrin Lorenz, Dieter Kadereit, Michael Wagner
Dual activation of the glucagon-like peptide 1 (GLP-1) and glucagon receptor has the potential to lead to a novel therapy principle for the treatment of diabesity. Here, we report a series of novel peptides with dual activity on these receptors that were discovered by rational design. On the basis of sequence analysis and structure-based design, structural elements of glucagon were engineered into the selective GLP-1 receptor agonist exendin-4, resulting in hybrid peptides with potent dual GLP-1/glucagon receptor activity...
May 5, 2017: Journal of Medicinal Chemistry
Cory A Bontrager, Tanner J Geibel, George A Lengyel
Unnatural amino acids, amino acids containing side-chain functionalities not commonly seen in nature, are increasingly found in synthetic peptide sequences. Synthesis of some unnatural amino acids often includes the use of a precursor consisting of a Schiff-base stabilized by a nickel cation. Unnatural side-chains can be installed on an amino acid backbone found in this Schiff-base complex. The resulting unnatural amino acid can then be isolated from this complex using hydrolysis of the Schiff-base, typically by employing reflux in strongly acidic solution...
April 6, 2017: Journal of Visualized Experiments: JoVE
Chuanling Zhang, Jiaqi Lu, Huizhong Su, Jing Yang, Demin Zhou
Cellular protrusion formation capacity is a key feature of developing neurons and many eukaryotic cells. However, the mechanisms underlying membrane growth in protrusion formation are largely unclear. In this study, photo-reactive unnatural amino acid 3-(3-methyl-3H-diazirin-3-yl)-propamino-carbonyl-Nε-l-lysine was incorporated by a genetic code expansion strategy into protrudin, a protein localized in acidic endosomes and in the endoplasmic reticulum, that induces cellular protrusion and neurite formation...
April 21, 2017: Scientific Reports
James S Italia, Yunan Zheng, Rachel E Kelemen, Sarah B Erickson, Partha S Addy, Abhishek Chatterjee
In the last two decades, unnatural amino acid (UAA) mutagenesis has emerged as a powerful new method to probe and engineer protein structure and function. This technology enables precise incorporation of a rapidly expanding repertoire of UAAs into predefined sites of a target protein expressed in living cells. Owing to the small footprint of these genetically encoded UAAs and the large variety of enabling functionalities they offer, this technology has tremendous potential for deciphering the delicate and complex biology of the mammalian cells...
April 15, 2017: Biochemical Society Transactions
László Csaba Bencze, Alina Filip, Gergely Bánóczi, Monica Ioana Toşa, Florin Dan Irimie, Ákos Gellért, László Poppe, Csaba Paizs
This study focuses on the expansion of the substrate scope of phenylalanine ammonia-lyase from Petroselinum crispum (PcPAL) towards the l-enantiomers of racemic styrylalanines rac-1a-d - which are less studied and synthetically challenging unnatural amino acids - by reshaping the aromatic binding pocket of the active site of PcPAL by point mutations. Ammonia elimination from l-styrylalanine (l-1a) catalyzed by non-mutated PcPAL (wt-PcPAL) took place with a 777-fold lower kcat/KM value than the deamination of the natural substrate, l-Phe...
May 3, 2017: Organic & Biomolecular Chemistry
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