Synthetic and Theoretical Studies for Cyclization Reactions to Form C-C and C-N Bonds
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Multiple Cellular Proteins Interact with LEDGF/P75 Through a Conserved Unstructured Consensus Motif
ARTICLE Received 19 Jan 2015 | Accepted 1 Jul 2015 | Published 6 Aug 2015 DOI: 10.1038/ncomms8968 Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif Petr Tesina1,2,3,*, Katerˇina Cˇerma´kova´4,*, Magdalena Horˇejsˇ´ı3, Katerˇina Procha´zkova´1, Milan Fa´bry3, Subhalakshmi Sharma4, Frauke Christ4, Jonas Demeulemeester4, Zeger Debyser4, Jan De Rijck4,**, Va´clav Veverka1,** & Pavlı´na Rˇeza´cˇova´1,3,** Lens epithelium-derived growth factor (LEDGF/p75) is an epigenetic reader and attractive therapeutic target involved in HIV integration and the development of mixed lineage leukaemia (MLL1) fusion-driven leukaemia. Besides HIV integrase and the MLL1-menin complex, LEDGF/p75 interacts with various cellular proteins via its integrase binding domain (IBD). Here we present structural characterization of IBD interactions with transcriptional repressor JPO2 and domesticated transposase PogZ, and show that the PogZ interaction is nearly identical to the interaction of LEDGF/p75 with MLL1. The interaction with the IBD is maintained by an intrinsically disordered IBD-binding motif (IBM) common to all known cellular partners of LEDGF/p75. In addition, based on IBM conservation, we identify and validate IWS1 as a novel LEDGF/p75 interaction partner. Our results also reveal how HIV integrase efficiently displaces cellular binding partners from LEDGF/p75. Finally, the similar binding modes of LEDGF/p75 interaction partners represent a new challenge for the development of selective interaction inhibitors. 1 Institute of Organic Chemistry and Biochemistry of the ASCR, v.v.i., Flemingovo nam. 2, 166 10 Prague, Czech Republic. 2 Department of Genetics and Microbiology, Faculty of Science, Charles University in Prague, Vinicna 5, 128 44 Prague, Czech Republic. -
Educator Materials Hands-On Activity HIV Reverse Transcription and AZT
Hands-on Activity HIV Reverse Transcription and AZT Educator Materials HIV REVERSE TRANSCRIPTION AND AZT OVERVIEW This hands-on activity is part of a series of activities and demonstrations focusing on various aspects of the human immunodeficiency virus (HIV) life cycle. In this activity, students will model how the anti-HIV drug AZT (azidothymidine) interferes with the process of viral replication and reduces the amount of virus in the Body. Students will first model reverse transcription, the process that results in the production of a double- stranded DNA copy of the HIV single-stranded RNA genome. (See introduction in the student document for a review of the process.) Using an actual HIV RNA sequence as a template, students will model the synthesis of a complementary strand of DNA By attaching nucleotides to one another. Then, students will demonstrate AZT’s effect on this process. They will suBstitute AZT in place of thymidine. AZT lacks a hydroxyl (OH) group that is necessary for suBsequent nucleotides to attach. When AZT is incorporated in a growing DNA sequence it prevents further nucleotides from Being added, thereby blocking the production of HIV DNA. Following this activity, it may Be helpful for students to complete the HIV integration activity. LEARNING OBJECTIVES Students will Be able to: • Code DNA from RNA. • Demonstrate the process of reverse transcription. • Understand the role of the enzyme reverse transcriptase in the formation of viral DNA. • Review the chemical structures of nucleic acids and identify structural -
The Total Synthesis of Securinine and Other Methodology Studies
University of Windsor Scholarship at UWindsor Electronic Theses and Dissertations Theses, Dissertations, and Major Papers 2010 The total synthesis of securinine and other methodology studies Bhartesh Dhudshia University of Windsor Follow this and additional works at: https://scholar.uwindsor.ca/etd Recommended Citation Dhudshia, Bhartesh, "The total synthesis of securinine and other methodology studies" (2010). Electronic Theses and Dissertations. 8275. https://scholar.uwindsor.ca/etd/8275 This online database contains the full-text of PhD dissertations and Masters’ theses of University of Windsor students from 1954 forward. These documents are made available for personal study and research purposes only, in accordance with the Canadian Copyright Act and the Creative Commons license—CC BY-NC-ND (Attribution, Non-Commercial, No Derivative Works). Under this license, works must always be attributed to the copyright holder (original author), cannot be used for any commercial purposes, and may not be altered. Any other use would require the permission of the copyright holder. Students may inquire about withdrawing their dissertation and/or thesis from this database. For additional inquiries, please contact the repository administrator via email ([email protected]) or by telephone at 519-253-3000ext. 3208. The Total Synthesis of Securinine and Other Methodology Studies by Bhartesh Dhudshia A Dissertation Submitted to the Faculty of Graduate Studies through the Department of Chemistry and Biochemistry in Partial Fulfillment of the Requirements -
Proviruses with Long-Term Stable Expression Accumulate In
viruses Article Proviruses with Long-Term Stable Expression Accumulate in Transcriptionally Active Chromatin Close to the Gene Regulatory Elements: Comparison of ASLV-, HIV- and MLV-Derived Vectors Dalibor Miklík 1,2, Filip Šenigl 1 and Jiˇrí Hejnar 1,* 1 Institute of Molecular Genetics, Czech Academy of Sciences, Videnska 1083, CZ-14220 Prague 4, Czech Republic; [email protected] (D.M.); [email protected] (F.S.) 2 Faculty of Science, Charles University, Albertov 6, CZ-12843 Prague 2, Czech Republic * Correspondence: [email protected] Received: 29 January 2018; Accepted: 6 March 2018; Published: 8 March 2018 Abstract: Individual groups of retroviruses and retroviral vectors differ in their integration site preference and interaction with the host genome. Hence, immediately after infection genome-wide distribution of integrated proviruses is non-random. During long-term in vitro or persistent in vivo infection, the genomic position and chromatin environment of the provirus affects its transcriptional activity. Thus, a selection of long-term stably expressed proviruses and elimination of proviruses, which have been gradually silenced by epigenetic mechanisms, helps in the identification of genomic compartments permissive for proviral transcription. We compare here the extent and time course of provirus silencing in single cell clones of the K562 human myeloid lymphoblastoma cell line that have been infected with retroviral reporter vectors derived from avian sarcoma/leukosis virus (ASLV), human immunodeficiency virus type 1 (HIV) and murine leukaemia virus (MLV). While MLV proviruses remain transcriptionally active, ASLV proviruses are prone to rapid silencing. The HIV provirus displays gradual silencing only after an extended time period in culture. -
HIV Integration Site Analysis of Cellular Models of HIV Latency with a Probe-Enriched Next-Generation Sequencing Assay
crossmark HIV Integration Site Analysis of Cellular Models of HIV Latency with a Probe-Enriched Next-Generation Sequencing Assay Sara Sunshine,a Rory Kirchner,b Sami S. Amr,c Leandra Mansur,c Rimma Shakhbatyan,c Michelle Kim,d,e Alberto Bosque,f Robert F. Siliciano,d,e Vicente Planelles,f Oliver Hofmann,b Shannan Ho Sui,b Jonathan Z. Lia Division of Infectious Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USAa; Bioinformatics Core, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USAb; Partners HealthCare Personalized Medicine, Cambridge, Massachusetts, USAc; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USAd; Howard Hughes Medical Institute, Chevy Chase, Maryland, USAe; Department of Pathology, University of Utah, Salt Lake City, Utah, USAf ABSTRACT Downloaded from Antiretroviral therapy (ART) is successful in the suppression of HIV but cannot target and eradicate the latent proviral reservoir. The location of retroviral integration into the human genome is thought to play a role in the clonal expansion of infected cells and HIV persistence. We developed a high-throughput targeted sequence capture assay that uses a pool of HIV-specific probes to enrich Illumina libraries prior to deep sequencing. Using an expanded clonal population of ACH-2 cells, we demonstrate that this sequence capture assay has an extremely low false-positive rate. This assay assessed four cellular models commonly used to -study HIV latency and latency-reversing agents: ACH-2 cells, J-Lat cells, the Bcl-2-transduced primary CD4؉ model, and the cul ؉ tured TCM (central memory) CD4 model. HIV integration site characteristics and genes were compared between these cellular models and to previously reported patient data sets. -
Functional Control of HIV-1 Post-Transcriptional Gene Expression by Host Cell Factors
Functional control of HIV-1 post-transcriptional gene expression by host cell factors DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Amit Sharma, B.Tech. Graduate Program in Molecular Genetics The Ohio State University 2012 Dissertation Committee Dr. Kathleen Boris-Lawrie, Advisor Dr. Anita Hopper Dr. Karin Musier-Forsyth Dr. Stephen Osmani Copyright by Amit Sharma 2012 Abstract Retroviruses are etiological agents of several human and animal immunosuppressive disorders. They are associated with certain types of cancer and are useful tools for gene transfer applications. All retroviruses encode a single primary transcript that encodes a complex proteome. The RNA genome is reverse transcribed into DNA, integrated into the host genome, and uses host cell factors to transcribe, process and traffic transcripts that encode viral proteins and act as virion precursor RNA, which is packaged into the progeny virions. The functionality of retroviral RNA is governed by ribonucleoprotein (RNP) complexes formed by host RNA helicases and other RNA- binding proteins. The 5’ leader of retroviral RNA undergoes alternative inter- and intra- molecular RNA-RNA and RNA-protein interactions to complete multiple steps of the viral life cycle. Retroviruses do not encode any RNA helicases and are dependent on host enzymes and RNA chaperones. Several members of the host RNA helicase superfamily are necessary for progressive steps during the retroviral replication. RNA helicase A (RHA) interacts with the redundant structural elements in the 5’ untranslated region (UTR) of retroviral and selected cellular mRNAs and this interaction is necessary to facilitate polyribosome formation and productive protein synthesis. -
The Role of Integration and Clonal Expansion in HIV Infection: Live Long and Prosper Elizabeth M
Anderson and Maldarelli Retrovirology (2018) 15:71 https://doi.org/10.1186/s12977-018-0448-8 Retrovirology REVIEW Open Access The role of integration and clonal expansion in HIV infection: live long and prosper Elizabeth M. Anderson and Frank Maldarelli* Abstract Integration of viral DNA into the host genome is a central event in the replication cycle and the pathogenesis of retroviruses, including HIV. Although most cells infected with HIV are rapidly eliminated in vivo, HIV also infects long-lived cells that persist during combination antiretroviral therapy (cART). Cells with replication competent HIV proviruses form a reservoir that persists despite cART and such reservoirs are at the center of eforts to eradicate or control infection without cART. The mechanisms of persistence of these chronically infected long-lived cells is uncer- tain, but recent research has demonstrated that the presence of the HIV provirus has enduring efects on infected cells. Cells with integrated proviruses may persist for many years, undergo clonal expansion, and produce replication competent HIV. Even proviruses with defective genomes can produce HIV RNA and may contribute to ongoing HIV pathogenesis. New analyses of HIV infected cells suggest that over time on cART, there is a shift in the composition of the population of HIV infected cells, with the infected cells that persist over prolonged periods having proviruses integrated in genes associated with regulation of cell growth. In several cases, strong evidence indicates the presence of the provirus in specifc genes may determine persistence, proliferation, or both. These data have raised the intrigu- ing possibility that after cART is introduced, a selection process enriches for cells with proviruses integrated in genes associated with cell growth regulation. -
Effects of Surface Oxygen-Containing Groups of the Flowerlike Carbon
catalysts Article Effects of Surface Oxygen-Containing Groups of the Flowerlike Carbon Nanosheets on Palladium Dispersion, Catalytic Activity and Stability in Hydrogenolytic Debenzylation of Tetraacetyldibenzylhexaazaisowurtzitane Yun Chen 1, Xinlei Ding 2, Wenge Qiu 2,* , Jianwei Song 3, Junping Nan 2, Guangmei Bai 2 and Siping Pang 1 1 School of Materials Science & Technology, Beijing Institute of Technology, Beijing 100081, China; [email protected] (Y.C.); [email protected] (S.P.) 2 Beijing Key Laboratory for Green Catalysis and Separation, College of Environmental and Energy Engineering, Beijing University of Technology, Beijing 100124, China; [email protected] (X.D.); [email protected] (J.N.); [email protected] (G.B.) 3 Qing Yang Chemical Industry Corporation, Liaoyang 111001, China; [email protected] * Correspondence: [email protected]; Tel.: +86-10-13521382103 Abstract: The influence of the surface chemical properties of the carbon support on the Pd dispersion, activity and stability of Pd(OH)2/C catalyst for the hydrogenolytic debenzylation of tetraacetyldiben- zylhexaazaisowurtzitane (TADB) was studied in detail. The flowerlike nanosheet carbon material (NSC) was chosen as the pristine support, meanwhile chemical oxidation with nitric acid and physical Citation: Chen, Y.; Ding, X.; Qiu, W.; calcination at 600 ◦C treatments were used to modify its surface properties, which were denoted as Song, J.; Nan, J.; Bai, G.; Pang, S. NSCox-2 (treated with 20 wt% HNO3) and NSC-600, respectively. The three carbon -
Ammonium Formate Catalytic Transfer Hydrogenation:A Convenient Method for Removal of Halogenated Benzyloxycarbonyl and Benzyl Protecting Groups in Peptide Synthesis
Indian Journal of Chemistry Vol. 39B, July 2000, pp. 504- 508 Ammonium formate catalytic transfer hydrogenation:A convenient method for removal of halogenated benzyloxycarbonyl and benzyl protecting groups in peptide synthesis D Channe G o wda·, B R ajesh & Shankare Gowd a Department of Studies in Chemistry, Uni versit y of Mysore, Manasagangotri , Mysore 570006, India Received 10 August ! 998; accepted (revised) 28 January 2000 A new appli cati on of ammonium fo rmate catalyti c transfer hydrogenolysis, in the presence of pall adised carbon, for removal of 2-chl orobenzyloxycarbony l (2-ClZ), 2,6-di chl orobenzyl (2,6-C 12Bzl), bro mobenzylo xycarbonyl (B rZ) and phenacyl ester (OPa) from amino acids, pepti des and hi gh molecul ar weight polymers is reported. Rapid and selecti ve removal of protecting groups un ti on and subsequent W:-branching were enhanced by der moderate, neutral and ambient conditions is often removal of the Boc group during each cycle by treat a necessary step in the a, rea of the peptide chemistry. ment for I hr with 50% TFA-CH2Ch when the Z A number of reagents have been developed for this group was used for N £-protection of lysine. purpose. The utility of ammonium formate in the Subsequently these problems were solved by em presence of I 0% palladium on carbon as reducin g pl oying more acid sta(?le 2-chlorobenzyloxycarbonyl agent for vari ous functi onal groups has been reviewed (2-CIZ) 11 group for W:-protection of lys in e and 2,6- 12 by Ram and Ehrenkanfer in 198i. -
Heterogeneous Catalytic Hydrogenation
•Platinum Metals Rev., 2012, 56, (4), 236–241• Heterogeneous Catalytic Hydrogenation Platinum group metals as hydrogenation catalysts in a two-day course http://dx.doi.org/10.1595/147106712X654187 http://www.platinummetalsreview.com/ Reviewed by Fabrizio Nerozzi Introduction Johnson Matthey, Catalysis and Chiral Technologies, Heterogeneous catalytic hydrogenations are important Orchard Road, Royston, Hertfordshire SG8 5HE, UK reactions that fi nd wide industrial application in Email: [email protected] the production of pharmaceuticals, agrochemicals, fi ne chemicals, fl avours, fragrances and dietary supplements. The reactions are generally highly selective and easy to work up, the catalyst can often be recovered and recycled, and the processes are atom effi cient. It is therefore no surprise that somewhere between 10–20% of the reactions used to produce chemicals today are catalytic hydrogenations. Despite the importance of the technique, and mainly because of its multidisciplinary nature, development chemists and engineers have a hard time fi nding training on this highly specialised subject. Scientifi c Update has fi lled this gap with a training course run for the fi rst time on the 16th and 17th of April 2012, in Brussels, Belgium (1). Attended by 35 scientists from 10 European countries and the USA, representing 27 chemical companies and research institutions, the course was an extensive scientifi c overview of heterogeneous catalytic hydrogenation, but also touched on engineering, safety and economic topics. The tutor was Felix Roessler, a catalysis expert who during his long career has worked at Roche and DSM, was honoured twice with the Sandmeyer Award granted by the Swiss Chemical Society (2), has authored 18 publications or monographs and holds 4 patents. -
Constrained Mutational Sampling of Amino Acids in HIV-1 Protease Evolution
bioRxiv preprint doi: https://doi.org/10.1101/354597; this version posted January 28, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Constrained mutational sampling of amino acids in HIV-1 protease evolution Jeffrey I. Boucher1,*, Troy W. Whitfield2,3,*, Ann Dauphin4, Gily Nachum1, Carl Hollins III1, Konstantin B. Zeldovich4, Ronald Swanstrom5, Celia A. Schiffer1, Jeremy Luban2,4, Daniel N. A. Bolon1,# 1Department of Biochemistry and Molecular Pharmacology, 2Department of Medicine, 3Program in Bioinformatics and Integrative Biology, 4Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA 5Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC USA *Co-first authors #Corresponding Author bioRxiv preprint doi: https://doi.org/10.1101/354597; this version posted January 28, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Abstract The evolution of HIV-1 protein sequences should be governed by a combination of factors including nucleotide mutational probabilities, the genetic code, and fitness. The impact of these factors on protein sequence evolution are interdependent, making it challenging to infer the individual contribution of each factor from phylogenetic analyses alone. We investigated the protein sequence evolution of HIV-1 by determining an experimental fitness landscape of all individual amino acid changes in protease. -
Disruption of the Terminal Base Pairs of Retroviral DNA During Integration
Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Disruption of the terminal base pairs of retroviral DNA during integration Brian P. Scottoline/ Samson Chow,^"* Viola Ellison/'^ and Patrick O. Brown^ 2,5 ^Department of Biochemistry, and ^Howard Hughes Medical Institute, Stanford University Medical School, Stanford, California 94305-5428 USA Integrase catalyzes two essential steps in the integration of the retroviral genome—end processing and strand transfer—both of which require the interaction of integrase with viral att sites located at the ends of viral genomic DNA. These two different polynucleotidyl transfer reactions are apparently carried out by a single active site. The end product of these reactions, the integrated provirus, does not undergo transposition and remains a stable part of the host cell genome. A central question in understanding the mechanism of integration is how a single active site accomplishes two distinct polynucleotidyl transfer reactions. We propose that integrase distorts DNA substrates to accommodate both reactions within the active site. Evidence is provided for disruption of base-pairing at the terminus of viral DNA during end processing. Furthermore, we show that this end fraying is a required step in end processing and that it appears to occur after initial binding of the viral DNA end. This requirement for base-pair disruption may account for the inability of integrase to use internal sites on DNA molecules as viral att sites. The specificity of integrase for DNA ends solves a problem posed by the long terminal repeat structure of the viral genome, and may help to prevent transposition of integrated proviruses.