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Methylation & HIV

Rita Meleddu, Simona Distinto, Angela Corona, Enzo Tramontano, Giulia Bianco, Claudia Melis, Filippo Cottiglia, Elias Maccioni
A series of 3-3-{2-[2-3-methyl-4-phenyl-2,3-dihydro-1,3-thiazol-2-ylidene]hydrazin-1-ylidene-2,3-dihydro-1H-indol-2-one derivatives has been designed and synthesized to study their activity on both HIV-1 (Human Immunodeficiency Virus type 1) RT (Reverse Transcriptase) associated functions. These derivatives are analogs of previously reported series whose biological activity and mode of action have been investigated. In this work we investigated the influence of the introduction of a methyl group in the position 3 of the dihydrothiazole ring and of a chlorine atom in the position 5 of the isatin nucleus...
October 21, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Gautam Srivastava, Adi Moseri, Naama Kessler, Sabine R Akabayov, Boris Arshava, Fred Naider, Jacob Anglister
Weak protein-protein and protein-ligand interactions play important roles in biological recognition. In many cases, simplification of structural studies of large protein complexes is achieved by investigation of the interaction between the protein and a weakly binding segment of its protein ligand. Detection of pairwise interactions in such complexes is a major challenge for both X-ray crystallography and NMR. We demonstrate that transferrednuclear Overhauser effect, TRNOE, in combination with asymmetric deuteration of a protein and a peptide ligand can be used to detect intermolecular interactions in large protein complexes with molecular weights up to ~100 kDa...
October 4, 2016: FEBS Journal
Brigitta G Baumert, Monika E Hegi, Martin J van den Bent, Andreas von Deimling, Thierry Gorlia, Khê Hoang-Xuan, Alba A Brandes, Guy Kantor, Martin J B Taphoorn, Mohamed Ben Hassel, Christian Hartmann, Gail Ryan, David Capper, Johan M Kros, Sebastian Kurscheid, Wolfgang Wick, Roelien Enting, Michele Reni, Brian Thiessen, Frederic Dhermain, Jacoline E Bromberg, Loic Feuvret, Jaap C Reijneveld, Olivier Chinot, Johanna M M Gijtenbeek, John P Rossiter, Nicolas Dif, Carmen Balana, Jose Bravo-Marques, Paul M Clement, Christine Marosi, Tzahala Tzuk-Shina, Robert A Nordal, Jeremy Rees, Denis Lacombe, Warren P Mason, Roger Stupp
BACKGROUND: Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors. METHODS: For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration...
September 26, 2016: Lancet Oncology
Hamid Alinejad-Rokny, Firoz Anwar, Shafagh Waters, Miles P Davenport, Diako Ebrahimi
The dinucleotide CpG is highly underrepresented in the genome of human immunodeficiency virus type 1 (HIV-1). To identify the source of CpG depletion in the HIV-1 genome we investigated two biological mechanisms: a) CpG methylation-induced transcriptional silencing and b) CpG recognition by Toll-like receptors (TLRs). We hypothesized that HIV-1 has been under selective evolutionary pressure by these mechanisms leading to the reduction of CpG in its genome. A CpG depleted genome would enable HIV-1 to avoid methylation-induced transcriptional silencing and/or to avoid recognition by TLRs that identify foreign CpG sequences...
September 28, 2016: Molecular Biology and Evolution
Xinyu Zhang, Amy C Justice, Ying Hu, Zuoheng Wang, Hongyu Zhao, Guilin Wang, Eric O Johnson, Brinda Emu, Richard E Sutton, John H Krystal, Ke Xu
Epigenetic control of human immunodeficiency virus-1 (HIV-1) genes is critical for viral integration and latency. However, epigenetic changes in the HIV-1-infected host genome have not been well characterized. Here, we report the first large-scale epigenome-wide association study of DNA methylation for HIV-1 infection. We recruited HIV-infected (n = 261) and uninfected (n = 117) patients from the Veteran Aging Cohort Study (VACS) and all samples were profiled for 485,521 CpG sites in DNA extracted from the blood...
August 12, 2016: Epigenetics: Official Journal of the DNA Methylation Society
Hong-Sheng Zhang, Guang-Yuan Du, Yang Liu, Zhong-Guo Zhang, Zhen Zhou, Hu Li, Ke-Qing Dai, Xiao-Ying Yu, Xiao-Meng Gou
Epigenetic modifications are thought to be important for gene expression changes during HIV-1 transcription and replication. The removal of histone H3 lysine27 (H3K27) trimethylation mark by UTX-1 is important for the robust induction of many specific genes during Tat-mediated HIV-1 transactvation. We found that UTX-1 enzymatic activity is needed for Tat to remove a repressive mark H3K27me3 in the HIV-1 long terminal repeat (LTR). UTX-1 converted the chromatin structure to a more transcriptionally active state by up-regulation of H3K4 methylation and down-regulation of H3K27 methylation on the specific regions of HIV-1 LTR...
September 23, 2016: International Journal of Biochemistry & Cell Biology
Mu-Chun Liu, Chin-Yih Chen, Chang-Hwa Chiang, Wei-Ming Wang, Richard P Cheng
The two lysine (Lys) residues in the human immunodeficiency virus trans-activator of transcription protein (HIV Tat protein) basic region (residues 47-57) are crucial for two bioactivities: RNA recognition and cellular uptake. Since the post-translational modifications of these two Lys residues affect the biological function of the Tat protein, we investigated the effect of methylation and acetylation of Lys50 and Lys51 in Tat-derived peptides on the two bioactivities. Tat-derived peptides, in which each lysine was replaced with a methylated- or acetylated-Lys, were synthesized by solid phase peptide synthesis...
November 1, 2016: Bioorganic & Medicinal Chemistry
Mira Hleyhel, Stéphanie Goujon, Jeanne Sibiude, Stephane Blanche, Josiane Warszawski
Ethyl methyl sulfone (EMS) contained in nelfinavir between 2007 and 2008 accidentally exposed embryos and fetuses to a powerful mutagen. We report data for 101 HIV-uninfected children exposed in utero included in the French prospective national cohort. The incidence of malformation was similar to that in the cohort as a whole with different drug exposures; no children had developed cancer after 9 years of follow up.
September 20, 2016: AIDS
Yanzhou Zhang, Vanitha Krishna Subbaiah, Deepa Rajagopalan, Cheng Yong Tham, Lissa Nurrul Abdullah, Tan Boon Toh, Min Gong, Tuan Zea Tan, Shweta Pradip Jadhav, Amit Kumar Pandey, Neerja Karnani, Edward Kai-Hua Chow, Jean Paul Thiery, Sudhakar Jha
HIV-Tat-interacting protein of 60 kDa (TIP60) is a lysine acetyltransferase and known to be downregulated in multiple cancers. Among various signalling pathways, TIP60 is implicated in regulating epithelial-mesenchymal transition (EMT). Here, we show that TIP60 expression abrogates cell migration and metastatic potential of breast cancer cells using in vitro and in vivo models. Mechanistically, we show that this is through its ability to destabilize DNMT1 and inhibit SNAIL2 function (SNAIL2-mediated EMT/cell migration)...
September 20, 2016: Journal of Molecular Cell Biology
Philip C Bevilacqua, Laura E Ritchey, Zhao Su, Sarah M Assmann
Single-stranded RNA molecules fold into extraordinarily complicated secondary and tertiary structures as a result of intramolecular base pairing. In vivo, these RNA structures are not static. Instead, they are remodeled in response to changes in the prevailing physicochemical environment of the cell and as a result of intramolecular base pairing and interactions with RNA-binding proteins. Remarkable technical advances now allow us to probe RNA secondary structure at single-nucleotide resolution and genome wide, both in vitro and in vivo...
September 14, 2016: Annual Review of Genetics
Aws M Hamdy, Zien Khaddour, Najim A Al-Masoudi, Qamar Rahman, Christian Hering-Junghans, Alexander Villinger, Peter Langer
Arylated coumarins were prepared by site-selective Suzuki-Miyaura cross-coupling reaction of the bis(triflate) of 4-methyl-6,7-dihydroxycoumarin. Triarylated coumarins were prepared by Suzuki-Miyaura cross-coupling reactions of 3-bromo-4-methyl-2-oxo-2H-chromene-6,7-diylbis(trifluoromethanesulfonate). The in vitro anti-HIV activity of the products was investigated. Two lead structures with considerable activities were identified.
November 1, 2016: Bioorganic & Medicinal Chemistry
Pejman Rahimian, Johnny J He
BACKGROUND: Synaptodendritic damage is a pathological hallmark of HIV-associated neurocognitive disorders, and HIV-1 Tat protein is known to cause such injury in the central nervous system. In this study, we aimed to determine the molecular mechanisms of Tat-induced neurite shortening, specifically the roles of miR-132, an important regulator of neurite morphogenesis in this process. METHODS: The relationship between Tat expression and miR-132 expression was first determined using reverse transcription quantitative PCR (qRT-PCR) in Tat-transfected astrocytes and neurons, astrocytes from Tat-transgenic mice, and HIV-infected astrocytes...
2016: Journal of Neuroinflammation
Michael J Corley, Christian Dye, Michelle L D'Antoni, Mary Margaret Byron, Kaahukane Leite-Ah Yo, Annette Lum-Jones, Beau Nakamoto, Victor Valcour, Ivo SahBandar, Cecilia M Shikuma, Lishomwa C Ndhlovu, Alika K Maunakea
Monocytes/macrophages contribute to the neuropathogenesis of HIV-related cognitive impairment (CI); however, considerable gaps in our understanding of the precise mechanisms driving this relationship remain. Furthermore, whether a distinct biological profile associated with HIV-related CI resides in immune cell populations remains unknown. Here, we profiled DNA methylomes and transcriptomes of monocytes derived from HIV-infected individuals with and without CI using genome-wide DNA methylation and gene expression profiling...
2016: Scientific Reports
Inder Pal Singh, Purvi Shah
INTRODUCTION: 1,2,3,4-Tetrahydroisoquinoline (THIQ) is one of the "privileged scaffolds", commonly found in nature. Initially, this class of compounds was known for its neurotoxicity. Later on, 1-methyl-1,2,3,4-tetrahydroisoquinoline was proved as an endogeneous Parkinsonism-preventing agent in mammals. The fused THIQs have been studied for their role as anticancer antibiotics. The US FDA approval of the trabectedin for the treatment of soft tissue sarcomas, is a milestone in the anticancer drug discovery...
September 13, 2016: Expert Opinion on Therapeutic Patents
Silvia Franchini, Umberto M Battisti, Claudia Sorbi, Annalisa Tait, Andrea Cornia, Lak Shin Jeong, Sang Kook Lee, Jayoung Song, Roberta Loddo, Silvia Madeddu, Giuseppina Sanna, Livio Brasili
Nucleoside analogues play an important role in antiviral, antibacterial and antineoplastic chemotherapy. Herein we report the synthesis, structural characterization and biological activity of some 4'-C -methyl- and -phenyl dioxolane-based nucleosides. In particular, α and β anomers of all natural nucleosides were obtained and characterized by NMR, HR-MS and X-ray crystallography. The compounds were tested for antimicrobial activity against some representative human pathogenic fungi, bacteria and viruses. Antitumor activity was evaluated in a large variety of human cancer cell-lines...
September 11, 2016: Archives of Pharmacal Research
Nwet Nwet Win, Takuya Ito, Yi Yi Win, Hla Ngwe, Takeshi Kodama, Ikuro Abe, Hiroyuki Morita
Viral protein R (Vpr) is an accessory protein that plays important roles in the viral pathogenesis of Human Immunodeficiency Virus-1 (HIV-1). An assay for anti-Vpr activity, using TREx-HeLa-Vpr cells, is a promising strategy to discover Vpr inhibitors. The anti-Vpr assay revealed that the CHCl3-soluble extract of Picrasma javanica bark possesses potent anti-Vpr activity. Furthermore, studies of quassinoids (1-15) previously isolated from the extract demonstrated that all of the tested quassinoids exhibit anti-Vpr activity...
October 1, 2016: Bioorganic & Medicinal Chemistry Letters
Angela Ciuffi
No abstract text is available yet for this article.
2016: Nature Microbiology
Gianluigi Lichinchi, Shang Gao, Yogesh Saletore, Gwendolyn Michelle Gonzalez, Vikas Bansal, Yinsheng Wang, Christopher E Mason, Tariq M Rana
N(6)-methyladenosine (m(6)A) is the most prevalent internal modification of eukaryotic mRNA. Very little is known of the function of m(6)A in the immune system or its role in host-pathogen interactions. Here, we investigate the topology, dynamics and bidirectional influences of the viral-host RNA methylomes during HIV-1 infection of human CD4 T cells. We show that viral infection triggers a massive increase in m(6)A in both host and viral mRNAs. In HIV-1 mRNA, we identified 14 methylation peaks in coding and noncoding regions, splicing junctions and splicing regulatory sequences...
2016: Nature Microbiology
Hao Wu, Guillaume Mousseau, Sonia Mediouni, Susana T Valente, Thomas Kodadek
We present here an efficient alternative to N-methylation for the purpose of morphing protein-binding peptides into more serum-stable and cell-permeable compounds. This involves the incorporation of a cycloalanine (CyAla) into a peptide in a way that avoids difficult coupling steps. We demonstrate the utility of this chemistry in creating a cell-permeable derivative of a high-affinity HIV Rev protein-binding peptide.
October 4, 2016: Angewandte Chemie
John L Goodier
Retrotransposons have generated about 40 % of the human genome. This review examines the strategies the cell has evolved to coexist with these genomic "parasites", focussing on the non-long terminal repeat retrotransposons of humans and mice. Some of the restriction factors for retrotransposition, including the APOBECs, MOV10, RNASEL, SAMHD1, TREX1, and ZAP, also limit replication of retroviruses, including HIV, and are part of the intrinsic immune system of the cell. Many of these proteins act in the cytoplasm to degrade retroelement RNA or inhibit its translation...
2016: Mobile DNA
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