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Methylation & HIV

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https://www.readbyqxmd.com/read/29140109/host-methyltransferases-and-demethylases-potential-new-epigenetic-targets-for-hiv-cure-strategies-and-beyond
#1
Daniela Boehm, Melanie Ott
A successful HIV cure strategy may require reversing HIV latency to purge hidden viral reservoirs or enhancing HIV latency to permanently silence HIV transcription. Epigenetic modifying agents show promise as antilatency therapeutics in vitro and ex vivo, but also affect other steps in the viral life cycle. In this review, we summarize what we know about cellular DNA and protein methyltransferases (PMTs) as well as demethylases involved in HIV infection. We describe the biology and function of DNA methyltransferases, and their controversial role in HIV infection...
November 2017: AIDS Research and Human Retroviruses
https://www.readbyqxmd.com/read/29121497/mannosylcalix-n-arenes-as-multivalent-ligands-for-dc-sign
#2
Ilaria Morbioli, Vanessa Porkolab, Andrea Magini, Alessandro Casnati, Franck Fieschi, Francesco Sansone
DC-SIGN is a receptor protruded from the membrane of immature dendritic cells (DCs) that participates in the activation of the immune response through the recognition of pathogen-associated molecular patterns (PAMPs). On the other hand, HIV exploits the interaction between high-mannose structures of its envelope glycoprotein gp120 and DC-SIGN to be transported towards and infect T-cells. DC-SIGN is involved in the recognition process in the form of a tetramer and the multiple exposition of carbohydrate recognition sites (CRSs) is amplified by the formation on the DCs membrane of patches of tetramers...
October 31, 2017: Carbohydrate Research
https://www.readbyqxmd.com/read/29081786/probing-the-single-key-amino-acid-responsible-for-the-novel-catalytic-function-of-ent-kaurene-oxidase-supported-by-nadph-cytochrome-p450-reductases-in-tripterygium-wilfordii
#3
Ping Su, Hongyu Guan, Yifeng Zhang, Xing Wang, Linhui Gao, Yujun Zhao, Tianyuan Hu, Jiawei Zhou, Baowei Ma, Lichan Tu, Yuru Tong, Luqi Huang, Wei Gao
Tripterygium wilfordii produces not only ent-kaurene, which is an intermediate of gibberellin (GA) biosynthesis in flowering plants, but also 16α-hydroxy-ent-kaurane, whose physiological role has not been characterized. The two compounds are biosynthesized from the universal diterpenoid precursor (E,E,E)-geranylgeranyl diphosphate (GGPP) by diterpene synthases, which have been discovered and functionally characterized in T. wilfordii. Here, we described the functional characterization of four cytochrome P450 reductases (TwCPR) and one ent-kaurene oxidase (TwKO)...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/29080495/application-of-the-morita-baylis-hillman-reaction-in-the-synthesis-of-3-n-cycloalkylbenzamido-methyl-2-quinolones-as-potential-hiv-1-integrase-inhibitors
#4
Khethobole C Sekgota, Swarup Majumder, Michelle Isaacs, Dumisani Mnkandhla, Heinrich C Hoppe, Setshaba D Khanye, Frederik H Kriel, Judy Coates, Perry T Kaye
A practicable six-step synthetic pathway has been developed to access a library of novel 3-[(N-cycloalkylbenzamido)methyl]-2-quinolones using Morita-Baylis-Hillman methodology. These compounds and their 3-[(N-cycloalkylamino)methyl]-2-quinolone precursors have been screened as potential HIV-1 integrase (IN) inhibitors. A concomitant survey of their activity against HIV-1 protease and reverse-transcriptase reveals selective inhibition of HIV-1 IN.
September 22, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28969577/14-formyl-15-aryloxy-methoxymatrine-and-14-aryloxymethylidenylmatrine-derivatives-as-anti-hiv-1-agents
#5
Jiulin Huang, Si-Ying Xiang, Min Lv, Liu-Meng Yang, Yuanyuan Zhang, Yong-Tang Zheng, Hui Xu
BACKGROUND: The human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) has always been the global health threat and the leading cause of deaths. However, due to the emergence of drug-resistant HIV, an inevitable consequence of increasing use of antiretroviral drugs posed a major threat to antiretroviral therapy success. OBJECTIVE: The discovery of anti-HIV-1 agents will be used for the effective treatment of HIV/AIDS. METHOD: In continuation of our program aimed to discover anti-HIV-1 agents, twelve matrine derivatives, such as 14-formyl-15-aryloxy/methoxymatrines (3a-j) and 14-aryloxymethylidenylmatrines (3k,l), were semi-prepared from matrine, and evaluated against HIV-1ⅢB replication in acutely infected C8166 cells in vitro...
October 2, 2017: Medicinal Chemistry
https://www.readbyqxmd.com/read/28969531/kidney-transplant-in-a-human-immunodeficiency-virus-positive-patient-case-report-of-drug-interactions
#6
Mümtaz Yılmaz, Deniz Gökengin, Osman Bozbıyık, Cüneyt Hoşcoşkun, Ayşe Uyan, Hüseyin Töz
End-stage renal disease in the human immunodeficiency virus-positive population is increasing. Kidney transplant is the optimal therapy for this population rather than dialysis modalities if some criteria are met. These include undetectable plasma human immunodeficiency virus RNA, CD4 cell count over 200 cells/μL, and the absence of any AIDS-defining illness. Here, we describe the first living-donor kidney transplant in a human immunodeficiency virus-positive recipient in Turkey. The patient, a 52-year-old male diagnosed as human immunodeficiency virus positive, was on antiretroviral therapy, which consisted of 400 mg twice daily darunavir, 100 mg/day ritonavir, and 50 mg/day dolutegravir...
September 30, 2017: Experimental and Clinical Transplantation
https://www.readbyqxmd.com/read/28953888/cg-dinucleotide-suppression-enables-antiviral-defence-targeting-non-self-rna
#7
Matthew A Takata, Daniel Gonçalves-Carneiro, Trinity M Zang, Steven J Soll, Ashley York, Daniel Blanco-Melo, Paul D Bieniasz
Vertebrate genomes exhibit marked CG suppression-that is, lower than expected numbers of 5'-CG-3' dinucleotides. This feature is likely to be due to C-to-T mutations that have accumulated over hundreds of millions of years, driven by CG-specific DNA methyl transferases and spontaneous methyl-cytosine deamination. Many RNA viruses of vertebrates that are not substrates for DNA methyl transferases mimic the CG suppression of their hosts. This property of viral genomes is unexplained. Here we show, using synonymous mutagenesis, that CG suppression is essential for HIV-1 replication...
October 5, 2017: Nature
https://www.readbyqxmd.com/read/28936074/syndromes-of-rapidly-progressive-cognitive-decline-our-experience
#8
Sadanandavalli Retnaswami Chandra, Lakshminarayanapuram Gopal Viswanathan, Anupama Ramakanth Pai, Rahul Wahatule, Suvarna Alladi
BACKGROUND: Dementias are fairly slowly progressive degenerative diseases of brain for which treatment options are very less and carry a lot of burden on family and society. A small percentage of them are rapidly progressive and mostly carry a different course outcome. However, there are no definite criteria other than the time line for these patients. AIMS: The aim of this was to identify and categorize the causes and course of rapidly progressive dementias seen in our center...
August 2017: Journal of Neurosciences in Rural Practice
https://www.readbyqxmd.com/read/28830144/layer-by-layer-engineered-microbicide-drug-delivery-system-targeting-hiv-1-gp120-physicochemical-and-biological-properties
#9
Fohona S Coulibaly, Miezan J M Ezoulin, Sudhaunshu S Purohit, Navid J Ayon, Nathan A Oyler, Bi-Botti C Youan
The purpose of this study was 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...
October 2, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28829212/targeting-methionine-cycle-as-a-potential-therapeutic-strategy-for-immune-disorders
#10
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
#11
Xunhai Zheng, Geoffrey A Mueller, Kyungmin Kim, Lalith Perera, Eugene F DeRose, Robert E London
Recent structural characterizations of the p51 and p66 monomers have established an important starting point for understanding the maturation pathway of the human immunodeficiency virus (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. 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...
September 24, 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
#12
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...
September 26, 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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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