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Dna-encoded library

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https://www.readbyqxmd.com/read/28220596/quantitative-pcr-is-a-valuable-tool-to-monitor-performance-of-dna-encoded-chemical-library-selections
#1
Yizhou Li, Gunther Zimmermann, Jörg Scheuermann, Dario Neri
Phage-display libraries and DNA-encoded chemical libraries (DECL) represent useful tools for the isolation of specific binding molecules out of large combinatorial sets of compounds. In both methods, specific binders are recovered at the end of affinity capture procedures, using target proteins of interest immobilized on a solid support. However, while the efficiency of phage-display selections is routinely quantified by counting the phage titer before and after the affinity capture step, no similar quantification procedures have been reported for the characterization of DNA-encoded chemical library selections...
February 21, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28220154/dna-display-of-folded-rna-libraries-enabling-rna-selex-without-reverse-transcription
#2
I S MacPherson, J S Temme, I J Krauss
A method for the physical attachment of folded RNA libraries to their encoding DNA is presented as a way to circumvent the reverse transcription step during systematic evolution of RNA ligands by exponential enrichment (RNA-SELEX). A DNA library is modified with one isodC base to stall T7 polymerase and a 5' "capture strand" which anneals to the nascent RNA transcript. This method is validated in a selection of RNA aptamers against human α-thrombin with dissociation constants in the low nanomolar range. This method will be useful in the discovery of RNA aptamers and ribozymes containing base modifications that make them resistant to accurate reverse transcription...
February 21, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28199790/an-integrated-microfluidic-processor-for-dna-encoded-combinatorial-library-functional-screening
#3
Andrew B MacConnell, Alexander K Price, Brian M Paegel
DNA-encoded synthesis is rekindling interest in combinatorial compound libraries for drug discovery and in technology for automated and quantitative library screening. Here, we disclose a microfluidic circuit that enables whole-library functional screens of DNA-encoded compound beads. The device carries out library bead distribution into picoliter-scale assay reagent droplets, photochemical cleavage of compound from the bead, assay incubation, laser-induced fluorescence-based assay detection, and fluorescence-activated droplet sorting to isolate hits...
February 15, 2017: ACS Combinatorial Science
https://www.readbyqxmd.com/read/28197319/structure-based-design-of-non-natural-peptidic-macrocyclic-mcl-1-inhibitors
#4
Jeffrey W Johannes, Stephanie Bates, Carl Beigie, Matthew A Belmonte, John Breen, Shenggen Cao, Paolo A Centrella, Matthew A Clark, John W Cuozzo, Christoph E Dumelin, Andrew D Ferguson, Sevan Habeshian, David Hargreaves, Camil Joubran, Steven Kazmirski, Anthony D Keefe, Michelle L Lamb, Haiye Lan, Yunxia Li, Hao Ma, Scott Mlynarski, Martin J Packer, Philip B Rawlins, Daniel W Robbins, Haidong Shen, Eric A Sigel, Holly H Soutter, Nancy Su, Dawn M Troast, Haiyun Wang, Kate F Wickson, Chengyan Wu, Ying Zhang, Qiuying Zhao, Xiaolan Zheng, Alexander W Hird
Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound 1, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound 1 bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28161858/wheat-drought-responsive-wxpl-transcription-factors-regulate-cuticle-biosynthesis-genes
#5
Huihui Bi, Sukanya Luang, Yuan Li, Natalia Bazanova, Nikolai Borisjuk, Maria Hrmova, Sergiy Lopato
The cuticle forms a hydrophobic waxy layer that covers plant organs and provides protection from biotic and abiotic stresses. Transcription of genes responsible for cuticle formation is regulated by several types of transcription factors (TFs). Five orthologous to WAX PRODUCTION (WXP1 and WXP2) genes from Medicago truncatula were isolated from a cDNA library prepared from flag leaves and spikes of drought tolerant wheat (Triticum aestivum, breeding line RAC875) and designated TaWXP-like (TaWXPL) genes. Tissue-specific and drought-responsive expression of TaWXPL1D and TaWXPL2B was investigated by quantitative RT-PCR in two Australian wheat genotypes, RAC875 and Kukri, with contrasting glaucousness and drought tolerance...
February 4, 2017: Plant Molecular Biology
https://www.readbyqxmd.com/read/28151659/discovery-of-a-first-in-class-receptor-interacting-protein-1-rip1-kinase-specific-clinical-candidate-gsk2982772-for-the-treatment-of-inflammatory-diseases
#6
Philip A Harris, Scott B Berger, Jae U Jeong, Rakesh Nagilla, Deepak Bandyopadhyay, Nino Campobasso, Carol A Capriotti, Julie A Cox, Lauren Dare, Xiaoyang Dong, Patrick M Eidam, Joshua N Finger, Sandra J Hoffman, James Kang, Viera Kasparcova, Bryan W King, Ruth Lehr, Yunfeng Lan, Lara K Leister, John D Lich, Thomas T MacDonald, Nathan A Miller, Michael T Ouellette, Christina S Pao, Attiq Rahman, Michael A Reilly, Alan R Rendina, Elizabeth J Rivera, Michelle C Schaeffer, Clark A Sehon, Robert R Singhaus, Helen H Sun, Barbara A Swift, Rachel D Totoritis, Anna Vossenkamper, Paris Ward, David D Wisnoski, Daohua Zhang, Robert W Marquis, Peter J Gough, John J Bertin
RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein we report our lead-optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis and ulcerative colitis...
February 2, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28130548/allosteric-beta-blocker-isolated-from-a-dna-encoded-small-molecule-library
#7
Seungkirl Ahn, Alem W Kahsai, Biswaranjan Pani, Qin-Ting Wang, Shuai Zhao, Alissa L Wall, Ryan T Strachan, Dean P Staus, Laura M Wingler, Lillian D Sun, Justine Sinnaeve, Minjung Choi, Ted Cho, Thomas T Xu, Gwenn M Hansen, Michael B Burnett, Jane E Lamerdin, Daniel L Bassoni, Bryant J Gavino, Gitte Husemoen, Eva K Olsen, Thomas Franch, Stefano Costanzi, Xin Chen, Robert J Lefkowitz
The β2-adrenergic receptor (β2AR) has been a model system for understanding regulatory mechanisms of G-protein-coupled receptor (GPCR) actions and plays a significant role in cardiovascular and pulmonary diseases. Because all known β-adrenergic receptor drugs target the orthosteric binding site of the receptor, we set out to isolate allosteric ligands for this receptor by panning DNA-encoded small-molecule libraries comprising 190 million distinct compounds against purified human β2AR. Here, we report the discovery of a small-molecule negative allosteric modulator (antagonist), compound 15 [([4-((2S)-3-(((S)-3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)amino)-2-(2-cyclohexyl-2-phenylacetamido)-3-oxopropyl)benzamide], exhibiting a unique chemotype and low micromolar affinity for the β2AR...
January 27, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28127897/cell-free-translational-screening-of-an-expression-sequence-tag-library-of-clonorchis-sinensis-for-novel-antigen-discovery
#8
Devi Kasi, Christy Catherine, Seung-Won Lee, Kyung-Ho Lee, Yu Jung Kim, Myeong Ro Lee, Jung Won Ju, Dong-Myung Kim
The rapidly evolving cloning and sequencing technologies have enabled understanding of genomic structure of parasite genomes, opening up new ways of combatting parasite-related diseases. To make the most of the exponentially accumulating genomic data, however, it is crucial to analyze the proteins encoded by these genomic sequences. In this study, we adopted an engineered cell-free protein synthesis system for large-scale expression screening of an expression sequence tag (EST) library of Clonorchis sinensis to identify potential antigens that can be used for diagnosis and treatment of clonorchiasis...
January 27, 2017: Biotechnology Progress
https://www.readbyqxmd.com/read/28127867/application-of-biocatalysis-to-on-dna-carbohydrate-library-synthesis
#9
Baptiste Thomas, Xiaojie Lu, William Birmingham, Kun Huang, Peter Both, Juana Reyes Martinez, Robert Young, Christopher Davie, Sabine Flitsch
DNA-encoded libraries are increasingly used for the discovery of bioactive lead compounds in high-throughput screening programmes against specific biological targets. Although a number of libraries are now available, they cover limited chemical space due to bias in ease of synthesis and the lack of chemical reactions that are compatible with DNA-tagging. For example, compound libraries rarely contain complex biomolecules such as carbohydrates with high level of functionality, stereochemistry and hydrophilicity...
January 26, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28094476/dna-encoded-compound-libraries-as-open-source-a%C3%A2-powerful-pathway-to-new-drugs
#10
EDITORIAL
Richard A Lerner, Sydney Brenner
"… We envisioned an iterative system where a unique DNA tag identifier that encoded the event was appended to each newly formed molecule. These vast collections of molecules are known today as DNA- encoded chemical libraries (DECLs), and allow scientists to do selections on the benchtop that previously required access to large and complex high-throughput screening centers …" Read more in the Guest Editorial by Richard A. Lerner and Sydney Brenner.
January 24, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28067010/hit-validation-methodologies-for-ligands-isolated-from-dna-encoded-chemical-libraries
#11
Gunther Zimmermann, Yizhou Li, Ulrike Rieder, Martin Mattarella, Dario Neri, Jörg Scheuermann
DNA-encoded chemical libraries (DECLs) are large collections of compounds linked to DNA fragments, serving as amplifiable barcodes, which can be screened on target proteins of interest. In typical DECL selections, preferential binders are identified by high-throughput DNA sequencing, comparing their frequency before and after the affinity capture step. Hits identified in this procedure need to be confirmed, by resynthesis and by performing affinity measurements. In this article, we present novel methods, based on the hybridization of oligonucleotide conjugates with fluorescently-labeled complementary oligonucleotides, which facilitate the determination of affinity constants and kinetic dissociation constants...
January 9, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28056160/discovery-of-a-potent-btk-inhibitor-with-a-novel-binding-mode-using-parallel-selections-with-a-dna-encoded-chemical-library
#12
John W Cuozzo, Paolo A Centrella, Diana Gikunju, Sevan Habeshian, Christopher D Hupp, Anthony D Keefe, Eric A Sigel, Holly H Soutter, Heather A Thomson, Ying Zhang, Matthew A Clark
We have identified and characterized novel potent inhibitors of Bruton's tyrosine kinase (BTK) from a single DNA encoded library of over 110 million compounds using multiple parallel selection conditions including variation in target concentration and addition of known binders to provide competition information. Distinct binding profiles were observed by comparing enrichments of library building-block combinations under these conditions; one enriched only at high concentrations of BTK and was competitive with ATP and another enriched at both high and low concentrations of BTK and was not competitive with ATP...
January 5, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28032411/achievements-challenges-and-opportunities-in-dna-encoded-library-research-an-academic-point-of-view
#13
Lik Hang Yuen, Raphael Franzini
DNA-encoded chemical libraries (DECLs) are pools of DNA-tagged small molecules that enable facile screening and identification of biomacromolecule binders. The successful development of DECLs has leads to their increasingly important role in drug development and screening hits have entered clinical trials. In this review, we summarize the development and currently active research areas of DECLs with a focus on contributions from groups at academic institutes. We further look at opportunities and future direction of DECL research in medicinal chemistry and chemical biology based on the symbiotic relationship between academia and industry...
December 29, 2016: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28011218/recent-advances-on-the-encoding-and-selection-methods-of-dna-encoded-chemical-library
#14
REVIEW
Bingbing Shi, Yu Zhou, Yiran Huang, Jianfu Zhang, Xiaoyu Li
DNA-encoded chemical library (DEL) has emerged as a powerful and versatile tool for ligand discovery in chemical biology research and in drug discovery. Encoding and selection methods are two of the most important technological aspects of DEL that can dictate the performance and utilities of DELs. In this digest, we have summarized recent advances on the encoding and selection strategies of DEL and also discussed the latest developments on DNA-encoded dynamic library, a new frontier in DEL research.
December 9, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28003936/towards-quantitative-viromics-for-both-double-stranded-and-single-stranded-dna-viruses
#15
Simon Roux, Natalie E Solonenko, Vinh T Dang, Bonnie T Poulos, Sarah M Schwenck, Dawn B Goldsmith, Maureen L Coleman, Mya Breitbart, Matthew B Sullivan
BACKGROUND: Viruses strongly influence microbial population dynamics and ecosystem functions. However, our ability to quantitatively evaluate those viral impacts is limited to the few cultivated viruses and double-stranded DNA (dsDNA) viral genomes captured in quantitative viral metagenomes (viromes). This leaves the ecology of non-dsDNA viruses nearly unknown, including single-stranded DNA (ssDNA) viruses that have been frequently observed in viromes, but not quantified due to amplification biases in sequencing library preparations (Multiple Displacement Amplification, Linker Amplification or Tagmentation)...
2016: PeerJ
https://www.readbyqxmd.com/read/27993012/rational-design-of-small-molecules-targeting-oncogenic-noncoding-rnas-from-sequence
#16
Matthew D Disney, Alicia J Angelbello
The discovery of RNA catalysis in the 1980s and the dissemination of the human genome sequence at the start of this century inspired investigations of the regulatory roles of noncoding RNAs in biology. In fact, the Encyclopedia of DNA Elements (ENCODE) project has shown that only 1-2% of the human genome encodes protein, yet 75% is transcribed into RNA. Functional studies both preceding and following the ENCODE project have shown that these noncoding RNAs have important roles in regulating gene expression, developmental timing, and other critical functions...
December 20, 2016: Accounts of Chemical Research
https://www.readbyqxmd.com/read/27984726/functional-segregation-of-overlapping-genes-in-hiv
#17
Jason D Fernandes, Tyler B Faust, Nicolas B Strauli, Cynthia Smith, David C Crosby, Robert L Nakamura, Ryan D Hernandez, Alan D Frankel
Overlapping genes pose an evolutionary dilemma as one DNA sequence evolves under the selection pressures of multiple proteins. Here, we perform systematic statistical and mutational analyses of the overlapping HIV-1 genes tat and rev and engineer exhaustive libraries of non-overlapped viruses to perform deep mutational scanning of each gene independently. We find a "segregated" organization in which overlapped sites encode functional residues of one gene or the other, but never both. Furthermore, this organization eliminates unfit genotypes, providing a fitness advantage to the population...
December 15, 2016: Cell
https://www.readbyqxmd.com/read/27957856/high-throughput-identification-of-dna-encoded-igg-ligands-that-distinguish-active-and-latent-mycobacterium-tuberculosis-infections
#18
Kimberly R Mendes, Marie Lynne Malone, John Maina Ndungu, Irena Suponitsky-Kroyter, Valerie J Cavett, Patrick J McEnaney, Andrew B MacConnell, Todd M Doran, Katharina Ronacher, Kim Stanley, Ofelia Utset, Gerhard Walzl, Brian M Paegel, Thomas Kodadek
The circulating antibody repertoire encodes a patient's health status and pathogen exposure history, but identifying antibodies with diagnostic potential usually requires knowledge of the antigen(s). We previously circumvented this problem by screening libraries of bead-displayed small molecules against case and control serum samples to discover "epitope surrogates" (ligands of IgGs enriched in the case sample). Here, we describe an improved version of this technology that employs DNA-encoded libraries and high-throughput FACS-based screening to discover epitope surrogates that differentiate noninfectious/latent (LTB) patients from infectious/active TB (ATB) patients, which is imperative for proper treatment selection and antibiotic stewardship...
January 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/27956228/genome-wide-crispr-screen-identifies-regulators-of-mapk-as-suppressors-of-liver-tumors-in-mice
#19
Chun-Qing Song, Yingxiang Li, Haiwei Mou, Jill Moore, Angela Park, Yotsawat Pomyen, Soren Hough, Zachary Kennedy, Andrew Fischer, Hao Yin, Daniel G Anderson, Darryl Conte, Lars Zender, Xin Wei Wang, Snorri Thorgeirsson, Zhiping Weng, Wen Xue
BACKGROUND & AIMS: It has been a challenge to identify liver tumor suppressors or oncogenes due to the genetic heterogeneity of these tumors. We performed a genome-wide screen to identify suppressors of liver tumor formation in mice, using CRISPR-mediated genome editing. METHODS: We performed a genome-wide CRISPR/Cas9-based knockout screen of P53-null mouse embryonic liver progenitor cells that overexpressed MYC. We infected p53(-/-);Myc;Cas9 hepatocytes with the mGeCKOa lentiviral library of 67,000 single-guide RNAs (sgRNAs), targeting 20,611 mouse genes, and transplanted the transduced cells subcutaneously into nude mice...
December 9, 2016: Gastroenterology
https://www.readbyqxmd.com/read/27934684/performing-yeast-one-hybrid-library-screens
#20
Juan I Fuxman Bass, John S Reece-Hoyes, Albertha J M Walhout
Yeast one-hybrid (Y1H) assays are used to identify which transcription factor (TF) "prey" molecules can bind a DNA fragment of interest that is used as "bait". Y1H assays involve introducing plasmids that encode TFs into a yeast "bait strain" in which the DNA fragment of interest is integrated upstream of one or more reporters, and activation of these reporters indicates that a TF-DNA interaction has occurred. These plasmids express each TF as a hybrid protein (hence the "one-hybrid" name) fused to the activation domain (AD) of the yeast TF Gal4...
December 1, 2016: Cold Spring Harbor Protocols
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