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Methylation & HIV

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https://www.readbyqxmd.com/read/28830144/layer-by-layer-engineered-microbicide-drug-delivery-system-targeting-hiv-1-gp120-physico-chemical-and-biological-properties
#1
Fohona S Coulibaly, Miezan J M Ezoulin, Sudhaunshu S Purohit, Navid J Avon, Nathan A Oyler, Bi Botti C Youan
The purpose of this study is to engineer a model anti-HIV microbicide (Tenofovir) drug delivery system targeting HIV-1 envelope glycoprotein gp120 (HIV-1 g120) for the prevention of HIV sexual transmission. HIV-1 g120 and mannose responsive particles (MRP) were prepared through the layer-by-layer coating of calcium carbonate (CaCO3) with Concanavalin A (Con A) and glycogen. MRP average particle size ranged from 881.7±15.45 nm to 1130±15.72 nm, depending on the number of Con A layers. Tenofovir encapsulation efficiency in CaCO3 was 74...
August 23, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28829212/targeting-methionine-cycle-as-a-potential-therapeutic-strategy-for-immune-disorders
#2
Heng Li, Huimin Lu, Wei Tang, Jianping Zuo
Methionine cycle plays an essential role in regulating many cellular events, especially transmethylation reactions, incorporating the methyl donor S-adenosylmethionine (SAM). The transmethylations and substances involved in the cycle have shown complicated effects and mechanisms on immunocytes developments and activations, and exert crucial impacts on the pathological processes in immune disorders. Areas covered: Methionine cycle has been considered as an effective means of drug developments. This review discussed the role of methionine cycle in immune responses and summarized the potential therapeutic strategies based on the cycle, including SAM analogs, methyltransferase inhibitors, S-adenosylhomocysteine hydrolase (SAHH) inhibitors, adenosine receptors specific agonists or antagonists and homocysteine (Hcy)-lowering reagents, in treating human immunodeficiency virus (HIV) infections, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), systemic sclerosis (SSc) and other immune disorders...
August 22, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28811321/identification-of-drivers-for-the-metamorphic-transition-of-hiv-1-reverse-transcriptase
#3
Xunhai Zheng, Geoffrey A Mueller, Kyungmin Kiim, Lalith Perera, Eugene F DeRose, Robert E London
Recent structural characterizations of the p51 and p66 monomers has established an important starting point for understanding the maturation pathway of the HIV-1 reverse transcriptase p66/p51 heterodimer. This process requires a metamorphic transition of the polymerase domain leading to formation of a p66/p66' homodimer that exists as a structural heterodimer. In order to better understand the drivers for this metamorphic transition, we have performed NMR studies of (15)N-labeled RT216 - a construct that includes the fingers and most of the palm domains...
August 15, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28770939/chemical-optimization-of-macrocyclic-hiv-1-inactivators-for-improving-potency-and-increasing-the-structural-diversity-at-the-triazole-ring
#4
Adel A Rashad, Kriti Acharya, Ann Haftl, Rachna Aneja, Alexej Dick, Andrew P Holmes, Irwin Chaiken
HIV-1 entry inhibition remains an urgent need for AIDS drug discovery and development. We previously reported the discovery of cyclic peptide triazoles (cPTs) that retain the HIV-1 irreversible inactivation functions of the parent linear peptides (PTs) and have massively increased proteolytic resistance. Here, in an initial structure-activity relationship investigation, we evaluated the effects of variations in key structural and functional components of the cPT scaffold in order to produce a platform for developing next-generation cPTs...
August 3, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28692545/selection-of-women-at-risk-for-cervical-cancer-in-an-hiv-infected-south-african-population
#5
Marjolein Van Zummeren, Wieke W Kremer, Matthys C Van Aardt, Erika Breytenbach, Karin L Richter, Lawrence Rozendaal, Birgit I Witte, Lise M A de Strooper, Albertus T Hesselink, Daniëlle A M Heideman, Peter J F Snijders, Renske D M Steenbergen, Greta Dreyer, Chris J L M Meijer
OBJECTIVE: Cervical cancer is the leading cause of cancer-related death in women in South Africa. This study evaluates DNA methylation levels in cervical (pre)cancer and aims to assess the value of high-risk human papillomavirus (hrHPV) testing and methylation analysis, alone or in combination, on physician-taken cervical scrapes to detect cervical cancer, and cervical intraepithelial neoplasia grade 3 (CIN3) in an HIV-infected South African population. DESIGN: Prospective observational multi-centre cohort study...
July 7, 2017: AIDS
https://www.readbyqxmd.com/read/28684413/a-crispr-cas9-approach-reveals-that-the-polymerase-activity-of-dna-polymerase-%C3%AE-is-dispensable-for-hiv-1-infection-in-dividing-and-nondividing-cells
#6
COMPARATIVE STUDY
Russell W Goetze, Dong-Hyun Kim, Raymond F Schinazi, Baek Kim
Retrovirus integration into the host genome relies on several host enzymes, potentially including DNA polymerase β (Pol β). However, whether human Pol β is essential for lentivirus replication in human cells is unclear. Here, we abolished DNA polymerase β (Pol β) expression by targeting its DNA polymerase domain with CRISPR/Cas9 in human monocytic THP-1 cells to investigate the role of Pol β in HIV-1 transduction in both dividing and nondividing macrophage stages of THP-1 cells. Pol β-knock-out was confirmed by enhanced sensitivity to methyl methanesulfonate-induced DNA damage...
August 25, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28638377/a-novel-bromodomain-inhibitor-reverses-hiv-1-latency-through-specific-binding-with-brd4-to-promote-tat-and-p-tefb-association
#7
Huachao Huang, Shuai Liu, Maxime Jean, Sydney Simpson, He Huang, Mark Merkley, Tsuyoshi Hayashi, Weili Kong, Irene Rodríguez-Sánchez, Xiaofeng Zhang, Hailemichael O Yosief, Hongyu Miao, Jianwen Que, James J Kobie, James Bradner, Netty G Santoso, Wei Zhang, Jian Zhu
While combinatory antiretroviral therapy (cART) can effectively reduce HIV-1 viremia, it cannot eliminate HIV-1 infection. In the presence of cART, viral reservoirs remain latent, impeding the cure of HIV-1/AIDS. Recently, latency-reversing agents (LRAs) have been developed with the intent of purging latent HIV-1, providing an intriguing strategy for the eradication of the residual viral reservoirs. Our earlier studies show that the first-generation, methyl-triazolo bromodomain, and extra-terminal domain inhibitor (BETi), JQ1, facilitates the reversal of HIV-1 latency...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28637181/crosstalk-between-histone-modifications-indicates-that-inhibition-of-arginine-methyltransferase-carm1-activity-reverses-hiv-latency
#8
Zheng Zhang, Bryan C Nikolai, Leah A Gates, Sung Yun Jung, Edward B Siwak, Bin He, Andrew P Rice, Bert W O'Malley, Qin Feng
In eukaryotic cells, the gene expression status is strictly controlled by epigenetic modifications on chromatin. The repressive status of chromatin largely contributes to HIV latency. Studies have shown that modification of histone H3K27 acts as a key molecular switch for activation or suppression of many cellular genes. In this study, we found that K27-acetylated histone H3 specifically recruited Super Elongation Complex (SEC), the transcriptional elongation complex essential for HIV-1 long terminal repeat (LTR)-mediated and general cellular transcription...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28539755/practical-synthesis-of-the-bicyclic-darunavir-side-chain-3r-3as-6ar-hexahydrofuro-2-3-b-furan-3-ol-from-monopotassium-isocitrate
#9
REVIEW
Gary L Moore, Rodger W Stringham, David S Teager, Tai-Yuen Yue
A practical synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol-a key intermediate in the synthesis of darunavir-from monopotassium isocitrate is described. The isocitric acid salt, obtained from a high-yielding fermentation fed by sunflower oil, was converted in several steps to a tertiary amide. This amide, along with the compound's ester functionalities, was reduced with lithium aluminum hydride to give, on acidic workup, a transient aminal-triol. This was converted in situ to the title compound, the bicyclic acetal furofuranol side chain of darunavir, a protease inhibitor used in treatment of HIV/AIDS...
January 20, 2017: Organic Process Research & Development
https://www.readbyqxmd.com/read/28494238/smyd2-mediated-histone-methylation-contributes-to-hiv-1-latency
#10
Daniela Boehm, Mark Jeng, Gregory Camus, Andrea Gramatica, Roland Schwarzer, Jeffrey R Johnson, Philip A Hull, Mauricio Montano, Naoki Sakane, Sara Pagans, Robert Godin, Steven G Deeks, Nevan J Krogan, Warner C Greene, Melanie Ott
Transcriptional latency of HIV is a last barrier to viral eradication. Chromatin-remodeling complexes and post-translational histone modifications likely play key roles in HIV-1 reactivation, but the underlying mechanisms are incompletely understood. We performed an RNAi-based screen of human lysine methyltransferases and identified the SET and MYND domain-containing protein 2 (SMYD2) as an enzyme that regulates HIV-1 latency. Knockdown of SMYD2 or its pharmacological inhibition reactivated latent HIV-1 in T cell lines and in primary CD4(+) T cells...
May 10, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28489061/microbial-natural-product-alternariol-5-o-methyl-ether-inhibits-hiv-1-integration-by-blocking-nuclear-import-of-the-pre-integration-complex
#11
Jiwei Ding, Jianyuan Zhao, Zhijun Yang, Ling Ma, Zeyun Mi, Yanbing Wu, Jiamei Guo, Jinmin Zhou, Xiaoyu Li, Ying Guo, Zonggen Peng, Tao Wei, Haisheng Yu, Liguo Zhang, Mei Ge, Shan Cen
While Highly Active Antiretroviral Therapy (HAART) has significantly decreased the mortality of human immunodeficiency virus (HIV)-infected patients, emerging drug resistance to approved HIV-1 integrase inhibitors highlights the need to develop new antivirals with novel mechanisms of action. In this study, we screened a library of microbial natural compounds from endophytic fungus Colletotrichum sp. and identified alternariol 5-O-methyl ether (AME) as a compound that inhibits HIV-1 pre-integration steps. Time-of addition analysis, quantitative real-time PCR, confocal microscopy, and WT viral replication assay were used to elucidate the mechanism...
May 10, 2017: Viruses
https://www.readbyqxmd.com/read/28476776/cytosine-methylation-by-dnmt2-facilitates-stability-and-survival-of-hiv-1-rna-in-the-host-cell-during-infection
#12
Rachana Roshan Dev, Rakesh Ganji, Satya Prakash Singh, Sundarasamy Mahalingam, Sharmistha Banerjee, Sanjeev Khosla
The enigmatic methyltransferase, DNMT2 (DNA methyltransferase 2), structurally resembles a DNA methyltransferase, but has been shown to be a tRNA methyltransferase targeting cytosine within a specific CpG in different tRNA molecules. We had previously shown that, during environmental stress conditions, DNMT2 is re-localized from the nucleus to the cytoplasmic stress granules (SGs) and is associated with RNA-processing proteins. In the present study, we show that DNMT2 binds and methylates various mRNA species in a sequence-independent manner and gets re-localized to SGs in a phosphorylation-dependent manner...
June 6, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28430394/structure-based-design-of-a-new-scaffold-for-cell-penetrating-peptidic-inhibitors-of-the-histone-demethylase-phf8
#13
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 Lys9 on histone H3 (H3K9me1/2), and is a transcriptional activator involved in the development and cancer. Affinity and specificity of PHF8 towards H3K9me2 is affected by interaction with both the catalytic domain and a PHD reader domain. The latter specifically recognizes tri-methylated Ly4 on histone H3. A fragment of the histone H3 tail with tri-methylated Lys4 was used as a template for the 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
#14
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...
June 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
#15
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
#16
REVIEW
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 5 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...
May 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28237978/longitudinal-study-of-surrogate-aging-measures-during-human-immunodeficiency-virus-seroconversion
#17
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
#18
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
#19
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...
February 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28148252/potential-of-zanthoxylum-leprieurii-as-a-source-of-active-compounds-against-drug-resistant-mycobacterium-tuberculosis
#20
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
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