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Dna-encoded library

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https://www.readbyqxmd.com/read/28094476/dna-encoded-compound-libraries-as-open-source-a%C3%A2-powerful-pathway-to-new-drugs
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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...
December 13, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27956228/genome-wide-crispr-screen-identifies-regulators-of-mapk-as-suppressors-of-liver-tumors-in-mice
#10
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
#11
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
https://www.readbyqxmd.com/read/27932801/dna-encoded-chemistry-enabling-the-deeper-sampling-of-chemical-space
#12
Robert A Goodnow, Christoph E Dumelin, Anthony D Keefe
DNA-encoded chemical library technologies are increasingly being adopted in drug discovery for hit and lead generation. DNA-encoded chemistry enables the exploration of chemical spaces four to five orders of magnitude more deeply than is achievable by traditional high-throughput screening methods. Operation of this technology requires developing a range of capabilities including aqueous synthetic chemistry, building block acquisition, oligonucleotide conjugation, large-scale molecular biological transformations, selection methodologies, PCR, sequencing, sequence data analysis and the analysis of large chemistry spaces...
December 9, 2016: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/27928112/an-enu-induced-p-c225s-missense-mutation-in-the-mouse-tgfb1-gene-does-not-cause-camurati-engelmann-disease-like-skeletal-phenotypes
#13
Satoki Ichimura, Shun Sasaki, Takuya Murata, Ryutaro Fukumura, Yoichi Gondo, Shiro Ikegawa, Tatsuya Furuichi
Camurati-Engelmann disease (CED) is a rare sclerosing bone disorder in humans with autosomal dominant inheritance. Mutations in the gene (TGFB1) that encodes transforming growth factor-β1 (TGF-β1) are causative for CED. TGF-β1 signaling is enhanced by the CED-causing mutations. In this study, we performed Tgfb1 mutation screening in an ENU-mutagenized mouse genomic DNA library. We identified a missense mutation in which cysteine was substituted by serine at position 225 (p.C225S), that corresponded to the CED-causing mutation (p...
December 8, 2016: Experimental Animals
https://www.readbyqxmd.com/read/27923918/identification-of-bicarbonate-as-a-trigger-and-genes-involved-with-extracellular-dna-export-in-mycobacterial-biofilms
#14
Sasha J Rose, Luiz E Bermudez
: Extracellular DNA (eDNA) is an integral biofilm matrix component of numerous pathogens, including nontuberculous mycobacteria (NTM). Cell lysis is the source of eDNA in certain bacteria, but the source of eDNA remains unidentified for NTM, as well as for other eDNA-containing bacterial species. In this study, conditions affecting eDNA export were examined, and genes involved with the eDNA export mechanism were identified. After a method for monitoring eDNA in real time in undisturbed biofilms was established, different conditions affecting eDNA were investigated...
December 6, 2016: MBio
https://www.readbyqxmd.com/read/27916887/cucumber-metallothionein-like-2-csmtl2-exhibits-metal-binding-properties
#15
Yu Pan, Yanglu Pan, Junpeng Zhai, Yan Xiong, Jinhua Li, Xiaobing Du, Chenggang Su, Xingguo Zhang
We identified a novel member of the metallothionein (MT) family, Cucumis sativus metallothionein-like 2 (CsMTL2), by screening a young cucumber fruit complementary DNA (cDNA) library. The CsMTL2 encodes a putative 77-amino acid Class II MT protein that contains two cysteine (Cys)-rich domains separated by a Cys-free spacer region. We found that CsMTL2 expression was regulated by metal stress and was specifically induced by Cd(2+) treatment. We investigated the metal-binding characteristics of CsMTL2 and its possible role in the homeostasis and/or detoxification of metals by heterologous overexpression in Escherichia coli cells...
November 30, 2016: Genes
https://www.readbyqxmd.com/read/27915375/identification-of-enzymes-responsible-for-extracellular-alginate-depolymerization-and-alginate-metabolism-in-vibrio-algivorus
#16
Hidetaka Doi, Yuriko Tokura, Yukiko Mori, Kenichi Mori, Yoko Asakura, Yoshihiro Usuda, Hiroo Fukuda, Akito Chinen
Alginate is a marine non-food-competing polysaccharide that has potential applications in biorefinery. Owing to its large size (molecular weight >300,000 Da), alginate cannot pass through the bacterial cell membrane. Therefore, bacteria that utilize alginate are presumed to have an enzyme that degrades extracellular alginate. Recently, Vibrio algivorus sp. SA2(T) was identified as a novel alginate-decomposing and alginate-utilizing species. However, little is known about the mechanism of alginate degradation and metabolism in this species...
December 3, 2016: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/27905914/development-of-a-gene-synthesis-platform-for-the-efficient-large-scale-production-of-small-genes-encoding-animal-toxins
#17
Ana Filipa Sequeira, Joana L A Brás, Catarina I P D Guerreiro, Renaud Vincentelli, Carlos M G A Fontes
BACKGROUND: Gene synthesis is becoming an important tool in many fields of recombinant DNA technology, including recombinant protein production. De novo gene synthesis is quickly replacing the classical cloning and mutagenesis procedures and allows generating nucleic acids for which no template is available. In addition, when coupled with efficient gene design algorithms that optimize codon usage, it leads to high levels of recombinant protein expression. RESULTS: Here, we describe the development of an optimized gene synthesis platform that was applied to the large scale production of small genes encoding venom peptides...
December 1, 2016: BMC Biotechnology
https://www.readbyqxmd.com/read/27905174/zirconium-iv-catalyzed-ring-opening-of-on-dna-epoxides-in-water
#18
Lijun Fan, Christopher P Davie
DNA-encoded library technology (ELT) has spurred wide interest in the pharmaceutical industry as a powerful tool for hit and lead generation. In recent years a number of "DNA-compatible" chemical modifications have been published and used to synthesize vastly diverse screening libraries. Herein we report a newly developed, zirconium tetrakis(dodecyl sulfate) [Zr(DS)4] catalyzed ring-opening of on-DNA epoxides in water with amines, including anilines. Subsequent cyclization of the resulting on-DNA β-amino alcohols leads to a variety of biologically interesting, non-aromatic heterocycles...
November 30, 2016: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/27900684/dna-rna-and-protein-based-stable-isotope-probing-for-high-throughput-biomarker-analysis-of-active-microorganisms
#19
Eleanor Jameson, Martin Taubert, Sara Coyotzi, Yin Chen, Özge Eyice, Hendrik Schäfer, J Colin Murrell, Josh D Neufeld, Marc G Dumont
Stable-isotope probing (SIP) enables researchers to target active populations within complex microbial communities, which is achieved by providing growth substrates enriched in heavy isotopes, usually in the form of (13)C, (18)O, or (15)N. After growth on the substrate and subsequent extraction of microbial biomarkers, typically nucleic acids or proteins, the SIP technique is used for the recovery and analysis of isotope-labeled biomarkers from active microbial populations. In the years following the initial development of DNA- and RNA-based SIP, it was common practice to characterize labeled populations by targeted gene analysis...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27877178/an-s-adenosyl-methionine-synthetase-sams-gene-from-andropogon-virginicus-l-confers-aluminum-stress-tolerance-and-facilitates-epigenetic-gene-regulation-in-arabidopsis-thaliana
#20
Bunichi Ezaki, Aiko Higashi, Norie Nanba, Takumi Nishiuchi
Candidate clones which conferred Al tolerance to yeast transformants (TFs) were obtained from a cDNA library derived from a highly Al-tolerant poaceae, Andropogon virginicus L. One such clone, AL3A-4, encoded an S-adenosyl methionine synthetase (SAMS) gene. A full-length cDNA was obtained by 5'-RACE, designated AvSAMS1, and introduced into Arabidopsis thaliana to investigate its biological functions under Al stress. Two TF plant lines both showed higher tolerance than the Col-0 ecotype (non-TF) not only for Al stress, but also for Cu, Pb, Zn and diamide stresses, suggesting the AvSAMS1 was a multiple tolerance gene...
2016: Frontiers in Plant Science
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