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Methylation & HIV

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https://www.readbyqxmd.com/read/28430394/structure-based-design-of-a-new-scaffold-for-cell-penetrating-peptidic-inhibitors-of-the-histone-demethylase-phf8
#1
Jerzy Dorosz, Lars Olsen, Signe Teuber Seger, Cornelia Steinhauer, Giorgos Bouras, Charlotte Helgstrand, Anders Wiuf, Michael Gajhede
The histone demethylase PHF8 catalyzes demethylation of mono- and di-methylated lysine 9 on histone H3 (H3K9me1/2) and is a transcriptional activator involved in development and cancer. Affinity and specificity of PHF8 towards H3K9me2 substrate is affected by interaction with both the catalytic domain and a PHD reader domain. The latter specifically recognizes tri-methylated lysine 4 on histone H3. A fragment of the histone H3 tail with tri-methylated lysine 4 was used as template for structure based design of a cyclic, cell-penetrating peptide that exhibits micromolar binding affinity to PHF8 in biochemical assays...
April 21, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28371664/synthesis-and-study-of-anti-hiv-1-rt-activity-of-5-benzoyl-4-methyl-1-3-4-5-tetrahydro-2h-1-5-benzodiazepin-2-one-derivatives
#2
Subhash Chander, Cheng-Run Tang, Helmi Mohammed Al-Maqtari, Joazaizulfazli Jamalis, Ashok Penta, Taibi Ben Hadda, Hasnah Mohd Sirat, Yong-Tang Zheng, Murugesan Sankaranarayanan
In the present study, a series of fourteen 5-benzoyl-4-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one derivatives were designed, synthesized and characterized by appropriate spectral analysis. Further, titled compounds were in-vitro screened against wild HIV-1 RT enzyme using ELISA based colorimetric assay, in which four compounds significantly inhibited the RT activity with IC50≤25µM. Moreover, two significantly active compounds of the series, A10 and A11 exhibited IC50 values 8.62 and 6.87µM respectively, during the in-vitro assay...
March 28, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28325289/specific-and-stable-suppression-of-hiv-provirus-expression-in%C3%A2-vitro-by-chimeric-zinc-finger-dna-methyltransferase-1
#3
Junxiao Deng, Xiying Qu, Panpan Lu, Xinyi Yang, Yuqi Zhu, Haiyan Ji, Yanan Wang, Zhengtao Jiang, Xian Li, Yangcheng Zhong, He Yang, Hanyu Pan, Won-Bin Young, Huanzhang Zhu
HIV-1 inserts its proviral DNA into the infected host cells, by which HIV proviral DNA can then be duplicated along with each cell division. Thus, provirus cannot be eradicated completely by current antiretroviral therapy. We have developed an innovative strategy to silence the HIV provirus by targeted DNA methylation on the HIV promoter region. We genetically engineered a chimeric DNA methyltransferase 1 composed of designed zinc-finger proteins to become ZF2 DNMT1. After transient transfection of the molecular clone encoding this chimeric protein into HIV-1 infected or latently infected cells, efficient suppression of HIV-1 expression by the methylation of CpG islands in 5'-LTR was observed and quantified...
March 17, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28250115/viral-epitranscriptomics
#4
Edward M Kennedy, David G Courtney, Kevin Tsai, Bryan R Cullen
Although it has been known for over 40 years that eukaryotic mRNAs bear internal base modifications, it is only in the last five years that the importance of these modifications has begun to come into focus. The most common mRNA modification, the addition of a methyl group to the N(6) position of adenosine (m(6)A), has been shown to affect splicing, translation and stability, and m(6)A is also essential for embryonic development in organisms ranging from plants to mice. While all viral transcripts examined so far have been found to be extensively m(6)A modified, the role, if any, of m(6)A in regulating viral gene expression and replication was previously unknown...
March 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28237978/longitudinal-study-of-surrogate-aging-measures-during-human-immunodeficiency-virus-seroconversion
#5
Janice M Leung, Nick Fishbane, Meaghan Jones, Alexander Morin, Stella Xu, Joseph Cy Liu, Julie MacIsaac, M-J Milloy, Kanna Hayashi, Julio Montaner, Steve Horvath, Michael Kobor, Don D Sin, P Richard Harrigan, S F Paul Man
Persons living with human immunodeficiency virus (HIV) harbor an increased risk of age-related conditions. We measured changes in telomere length and DNA methylation in the peripheral blood of 31 intravenous drug users, who were followed longitudinally with blood samples pre-HIV (T1), immediately post-HIV (T2; 1.9±1 year from T1), and at a later follow-up time (T3; 2.2±1 year from T2). Absolute telomere length measurements were performed using polymerase chain reaction methods. Methylation profiles were obtained using the Illumina Human Methylation450 platform...
February 23, 2017: Aging
https://www.readbyqxmd.com/read/28171682/unusual-electrospray-ionization-induced-fragmentation-structural-elucidation-of-an-in-process-synthetic-intermediate-of-doravirine-mk-1439-using-liquid-chromatography-high-resolution-tandem-mass-spectrometry-and-two-dimensional-nuclear-magnetic-resonance
#6
Huaming Sheng, Katrina W Lexa, Li-Kang Zhang, Rong-Sheng Yang, Timothy J Wright, Benjamin D Sherry, Roy Helmy, Gary E Martin
RATIONALE: During the development of a novel synthetic route to doravirine (1), a human immunodeficiency type 1 virus (HIV-1) nonnucleoside reverse transcriptase inhibitor (NNRTI), an unanticipated reaction intermediate, methyl (Z)-2-(3-chloro-5-cyanophenoxy)-5-(3-(3-chloro-5-cyanophenoxy)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5-ethoxy-3-(trifluoromethyl)pent-2-enoate (2), was isolated. Moreover, an unusual electrospray ionization (ESI)-induced fragmentation was observed for 2. Hence, efforts were made towards the understanding of the structure of 2, which was crucial for the understanding of the reaction mechanism...
April 30, 2017: Rapid Communications in Mass Spectrometry: RCM
https://www.readbyqxmd.com/read/28160944/dihydropyrimidinone-isatin-hybrids-as-novel-non-nucleoside-hiv-1-reverse-transcriptase-inhibitors
#7
Titiksh L Devale, Jignesh Parikh, Pankaj Miniyar, Pankaj Sharma, Birendra Shrivastava, Prashant Murumkar
A novel series of substituted N-(2-(2,3-dioxoindolin-1-yl)acetyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide was designed, synthesized and evaluated for in vitro Reverse Transcriptase (RT) inhibitory activity. This series is a combination of peculiar structural features from leading scaffolds of [(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) and oxyindole. In vitro screening led to identification of two hybrids (9c and 9d) possessing higher RT inhibitory activity than the standard rilpivirine...
January 18, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28148252/potential-of-zanthoxylum-leprieurii-as-a-source-of-active-compounds-against-drug-resistant-mycobacterium-tuberculosis
#8
Lydia Bunalema, Ghislain Wabo Fotso, Paul Waako, John Tabuti, Samuel O Yeboah
BACKGROUND: Tuberculosis (TB) is still a global health problem mainly due to development of resistance and co-infection with the Human immune Virus (HIV). Treatment of multi and extensively drug resistant TB requires use of second line drugs which are less efficacious, expensive and very toxic. This has necessitated a need to search for new treatment regimens especially from medicinal plants. Zanthoxylum leprieurii, a plant species from Rutaceae is used locally in the treatment of tuberculosis in Uganda...
February 2, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28114951/hiv-signaling-through-cd4-and-ccr5-activates-rho-family-gtpases-that-are-required-for-optimal-infection-of-primary-cd4-t-cells
#9
Mark B Lucera, Zach Fleissner, Caroline O Tabler, Daniela M Schlatzer, Zach Troyer, John C Tilton
BACKGROUND: HIV-1 hijacks host cell machinery to ensure successful replication, including cytoskeletal components for intracellular trafficking, nucleoproteins for pre-integration complex import, and the ESCRT pathway for assembly and budding. It is widely appreciated that cellular post-translational modifications (PTMs) regulate protein activity within cells; however, little is known about how PTMs influence HIV replication. Previously, we reported that blocking deacetylation of tubulin using histone deacetylase inhibitors promoted the kinetics and efficiency of early post-entry viral events...
January 24, 2017: Retrovirology
https://www.readbyqxmd.com/read/28101036/anti-n-methyl-d-aspartate-receptor-encephalitis-in-hiv-infection
#10
Eunice Patarata, Vera Bernardino, Ana Martins, Rui Pereira, Conceição Loureiro, Maria Francisca Moraes-Fontes
Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a rare condition characterized by emotional and behavioral disturbances, dyskinesias, and extrapyramidal signs. It occurs in young women of reproductive age and is classically described as a paraneoplastic phenomenon. We present a 36-year-old, HIV-positive female who was admitted to the hospital in an acute confusional state, with a stiff posture, periods of motor agitation, and myoclonic jerks of the hands. Her mental state progressively deteriorated...
September 2016: Case Reports in Neurology
https://www.readbyqxmd.com/read/28017762/structure-activity-relationship-studies-on-a-trp-dendrimer-with-dual-activities-against-hiv-and-enterovirus-a71-modifications-on-the-amino-acid
#11
Belén Martínez-Gualda, Liang Sun, Eva Rivero-Buceta, Aida Flores, Ernesto Quesada, Jan Balzarini, Sam Noppen, Sandra Liekens, Dominique Schols, Johan Neyts, Pieter Leyssen, Carmen Mirabelli, María-José Camarasa, Ana San-Félix
We have recently described a new class of dendrimers with tryptophan (Trp) on the surface that show dual antiviral activities against HIV and EV71 enterovirus. The prototype compound of this family is a pentaerythritol derivative with 12 Trps on the periphery. Here we complete the structure-activity relationship studies of this family to identify key features that might be significant for the antiviral activity. With this aim, novel dendrimers containing different amino acids (aromatic and non-aromatic), tryptamine (a "decarboxylated" analogue of Trp) and N-methyl Trp on the periphery have been prepared...
December 23, 2016: Antiviral Research
https://www.readbyqxmd.com/read/28010138/synthesis-molecular-modeling-and-biological-evaluation-of-two-new-chicoric-acid-analogs
#12
Giuliana Righi, Romina Pelagalli, Valerio Isoni, Ilaria Tirotta, Roberto Dallocchio, Alessandro Dessì, Beatrice Macchi, Caterina Frezza, Ilaria Rossetti, Paolo Bovicelli
Two conformationally constrained compounds similar to chicoric acid but lacking the catechol and carboxyl groups were prepared. In these analogues, the single bond between the two caffeoyl fragments has been replaced with a chiral oxirane ring and both aromatic residues modified protecting completely or partially the catechol moiety as methyl ether. Preliminary molecular modelling studies carried out on the two analogues showed interactions near the active site of HIV integrase; however, in comparison with raltegravir, the biological evaluation confirmed that CAA-1 and CAA-2 were unable to inhibit infection at lower concentration...
February 2017: Natural Product Research
https://www.readbyqxmd.com/read/28005232/hiv-1-glycoprotein-120-enhancement-of-n-methyl-d-aspartate-nmda-receptor-mediated-excitatory-postsynaptic-currents-implications-for-hiv-1-associated-neural-injury
#13
Yan Zhou, Jianuo Liu, Huangui Xiong
It is widely accepted that human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein 120 (gp120) plays an important role in HIV-1-induced neural injury and pathogenesis of HIV-1-associated dementia (HAND). Multiple pathways have been proposed for gp120-induced neurotoxicity, amongst is the activation of N-Methyl-D-Aspartate receptors (NMDARs). It has been shown that gp120 causes neuronal injury or death and gp120 transgenic mice exhibit neurological similarity to that of HAND, all of which can be blocked or attenuated by NMDAR antagonists...
December 22, 2016: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
https://www.readbyqxmd.com/read/27990142/homeostatically-maintained-resting-naive-cd4-t-cells-resist-latent-hiv-reactivation
#14
Yasuko Tsunetsugu-Yokota, Mie Kobayahi-Ishihara, Yamato Wada, Kazutaka Terahara, Haruko Takeyama, Ai Kawana-Tachikawa, Kenzo Tokunaga, Makoto Yamagishi, Javier P Martinez, Andreas Meyerhans
Homeostatic proliferation (HSP) is a major mechanism by which long-lived naïve and memory CD4(+) T cells are maintained in vivo and suggested to contribute to the persistence of the latent HIV-1 reservoir. However, while many in vitro latency models rely on CD4(+) T cells that were initially differentiated via T-cell receptor (TCR) stimulation into memory/effector cells, latent infection of naïve resting CD4(+) T cells maintained under HSP conditions has not been fully addressed. Here, we describe an in vitro HSP culture system utilizing the cytokines IL-7 and IL-15 that allows studying latency in naïve resting CD4(+) T cells...
2016: Frontiers in Microbiology
https://www.readbyqxmd.com/read/27978762/total-syntheses-of-anti-hiv-cyclodepsipeptides-aetheramides-a-and-b
#15
Na Qi, Zhanlong Wang, Srinivasa Rao Allu, Qiang Liu, Jian Guo, Yun He
A concise total synthesis of aetheramide A in an overall yield of 4.7% with a longest linear sequence of 15 steps is described. This synthetic strategy features macrocyclization via an intramolecular trapping of acylketene generated from dioxinone precursor, and stereoselective late-stage methylation of β-ketoamide. Aetheramide B could be synthesized via the ester migration of aetheramide A.
December 16, 2016: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/27941949/in-vitro-effects-of-the-small-molecule-protein-kinase-c-agonists-on-hiv-latency-reactivation
#16
Jessica Brogdon, Widade Ziani, Xiaolei Wang, Ronald S Veazey, Huanbin Xu
The persistence of latently HIV-infected cellular reservoirs represents the major obstacle to virus eradication in patients under antiretroviral therapy (ART). Cure strategies to eliminate these reservoirs are thus needed to reactivate proviral gene expression in latently infected cells. In this study, we tested optimal concentrations of PKC agonist candidates (PEP005/Ingenol-3-angelate, prostratin, bryostatin-1, and JQ1) to reactivate HIV latency in vitro, and examined their effects on cell survival, activation and epigenetic histone methylation after treatment alone or in combination in cell line and isolated CD4 T cells from SIV-infected macaques...
December 12, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27922854/identification-of-hiv-infection-related-dna-methylation-sites-and-advanced-epigenetic-aging-in-hiv-positive-treatment-naive-u-s-veterans
#17
Kristin N Nelson, Qin Hui, David Rimland, Ke Xu, Matthew S Freiberg, Amy C Justice, Vincent C Marconi, Yan V Sun
OBJECTIVE: HIV-positive individuals are at higher risk than healthy persons for aging-related diseases, including myocardial infarction and non-AIDS defining cancers. Recent evidence suggests that HIV infection may modulate changes in the host cell epigenome, and these changes represent a potential mechanism through which HIV infection accelerates aging. We assessed the difference in DNA methylation (DNAm) age, an aging marker involving multiple age-related cytosine-guanine dinucleotide (CpG) sites, among antiretroviral treatment (ART)-naive HIV-positive and HIV-negative individuals in a cohort of veterans from the Veterans Aging Cohort Study...
February 20, 2017: AIDS
https://www.readbyqxmd.com/read/27906000/the-antiviral-compound-bit225-inhibits-hiv-1-replication-in-myeloid-dendritic-cells
#18
Gabriela Khoury, Gary Ewart, Carolyn Luscombe, Michelle Miller, John Wilkinson
BACKGROUND: Previous studies with BIT225 (N-carbamimidoyl-5-(1-methyl-1H-pyrazol-4-yl)-2-naphthamide) have demonstrated a unique antiviral activity that blocks the release of HIV-1 from monocyte-derived macrophages (MDM). Antagonising the ion channel formed by HIV-1 Vpu, BIT225 preferentially targets de novo intracellular virus produced in 'virus-containing compartments' of MDM. In primary infections, dendritic cells (DC) are one of the first cells infected by HIV-1 and can transfer virus to more permissive CD4(+) T cells, making these cells an important target for novel antiviral therapies...
February 8, 2016: AIDS Research and Therapy
https://www.readbyqxmd.com/read/27860311/single-heteroatom-substitutions-in-the-efavirenz-oxazinone-ring-impact-metabolism-by-cyp2b6
#19
Philip M Cox, Namandjé N Bumpus
Previously, we observed that the oxazinone ring is important for cytochrome P450 2B6 (CYP2B6) activity toward efavirenz ((4S)-6-chloro-4-(2-cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one), a CYP2B6 substrate used to treat HIV. To further understand the structural characteristics of efavirenz that render it a CYP2B6 substrate, we tested the importance of each heteroatom of the oxazinone ring. We assembled a panel of five analogues: 6-chloro-4-(2-cyclopropylethynyl)-1,4-dihydro-2-methyl-4-(trifluoromethyl)-2H-3,1-benzoxazine (1), (4S)-6-chloro-4-[(1E)-2-cyclopropylethenyl]-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinazolinone (2), (4S)-6-chloro-4-(2-cyclopropylethynyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinazolinone (3), 6-chloro-4-(cyclopropylethynyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinolinone (4), and 6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]dioxin-2-one (5)...
December 6, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27854146/immunoassay-and-molecular-methods-to-investigate-dna-methylation-changes-in-peripheral-blood-mononuclear-cells-in-hiv-infected-patients-on-cart
#20
Adelina Rosca, Gabriela Anton, Luminita Ene, Iulia Iancu, Aura Temereanca, Cristian L Achim, Simona M Ruta
This study aimed to investigate the influence of antiretroviral therapy on methylation markers, in a group of HIV infected, heavily treated patients. Immune and molecular methods were used to investigate potential changes in methylation profile in DNA isolated from peripheral blood mononuclear cells collected from antiretroviral-experienced HIV infected patients and healthy controls. The percentage of 5-methylcytosine was inversely correlated with proviral DNA and active replication while DNMT1 (p = 0.01) and DNMT3A (p = 0...
November 17, 2016: Journal of Immunoassay & Immunochemistry
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