Anti-human immunodeficiency virus 1 (HIV-1) activities of 3-deazaadenosine analogs: increased potency against 3'-azido-3'-deoxythymidine-resistant HIV-1 strains.

Mayers, Douglas L.; Mikovits, Judy A.; Joshi, Bharat; Hewlett, Indira; Estrada, Joseph S.; Wolfe, Alan D.; Garcia, Gregory E.; Doctor, Bhupendra P.; Burke, Donald S.; Gordon, Richard K.; Lane, James R.; Chiang, Peter K.

doi:10.1073/pnas.92.1.215

Cited by 62 publications

(55 citation statements)

References 31 publications

(24 reference statements)

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“…Our work suggests the possibility that smallmolecule inhibitors of RNA methyltransferases might be a new class of anti-HIV-1 drugs. Indeed, we and others (62)(63)(64)(65) have found that treating cells with RNA methylation inhibitors can suppress HIV-1 replication (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

Trimethylguanosine capping selectively promotes expression of Rev-dependent HIV-1 RNAs

Yedavalli

Jeang

2010

Proc. Natl. Acad. Sci. U.S.A.

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5′-mRNA capping is an early modification that affects pre-mRNA synthesis/splicing, RNA cytoplasmic transport, and mRNA translation and turnover. In eukaryotes, a 7-methylguanosine (m7G) cap is added to newly transcribed RNA polymerase II (RNAP II) transcripts. A subset of RNAP II-transcribed cellular RNAs, including small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), and telomerase RNA, is further hypermethylated at the exocyclic N2 of the guanosine to create a trimethylguanosine (TMG)-capped RNA. Some of these TMG-capped RNAs are transported within the nucleus and from the nucleus to the cytoplasm by the CRM-1 (required for chromosome region maintenance) protein. CRM-1 is also used to export Rev/RRE-dependent unspliced/ partially spliced HIV-1 RNAs. Here we report that like snRNAs and snoRNAs, some Rev/RRE-dependent HIV-1 RNAs are TMG-capped. The methyltransferase responsible for TMG modification of HIV-1 RNAs is the human PIMT (peroxisome proliferator-activated receptor-interacting protein with methyltransferase) protein. TMG capping of unspliced/partially spliced HIV-1 RNAs represents a new regulatory mechanism for selective expression.required for chromosome region maintenance | RNA export | peroxisome proliferator-activated receptor-interacting protein with methyltransferase P osttranscriptional processing of RNA plays a critical role in gene expression (1-3). An early mRNA modification is the formation of a 7-methylguanosine (m7G) cap (4-6). In mammals, the acquisition of an m7G cap requires two enzymes (7-9), a capping enzyme (triphosphatase and guanylyltransferase activity) and an RNA-(guanine 7)-methyltransferase. These proteins are essential for cell growth, and mutations in the triphosphatase, guanylyltransferase, or methyltransferase components of the capping apparatus are lethal in vivo (10).Cellular RNAP II transcripts are mostly m7G-capped (1-3, 11). An m7G cap facilitates the initiation of translation in mammalian cells, and a failure to cap premRNAs results in their accelerated decay by 5′ exoribonuclease degradation (2,(12)(13)(14). Capping of viral RNAs has been less extensively investigated. It has been generally assumed that like cellular RNAs, many viral RNAs have a 5′ m7G cap, and that viruses either use the cellular capping machinery (e.g., viruses that replicate in the nucleus) or encode their own capping enzymes (e.g., viruses that replicate in the cytoplasm) (15, 16). Interestingly, there is a surprisingly diverse range of cap modifications; for instance, Mimivirus, a large DNA virus of amoeba, encodes an RNA cap guanine-N2 methyltransferase that hypermethylates the viral RNA cap (17); influenza virus "snatches" caps from cellular mRNAs (18, 19); West Nile fever virus has two methyl additions on its RNA cap (20); Sindbis virus produces mRNAs that have dimethylguanosine and trimethylguanosine caps [hypermethylated caps/m 2,2,7 G caps (21)]; and Semliki forest virus late mRNAs also have hypermethylated caps (22). On the other hand, poliovirus, encephalomyelitis virus, foot and mouth...

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Section: Discussionmentioning

confidence: 99%

Trimethylguanosine capping selectively promotes expression of Rev-dependent HIV-1 RNAs

Yedavalli

Jeang

2010

Proc. Natl. Acad. Sci. U.S.A.

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“…So, is DAA too toxic to use as an antiviral? In fact, several papers have reported using DAA to inhibit the replication of diverse viruses, including Rous sarcoma virus, HIV-1, respiratory syncytial virus, parainfluenza virus, vesicular stomatitis virus, measles virus, and reovirus (57)(58)(59)(60)(61), in cultured cells at concentrations that did not show any detectable cytopathic effects. Even more impressively, DAA was found to effectively block respiratory syncytial virus replication in cotton rats (58) and Ebola virus-induced fatality in mice (63,64) at doses that did not give rise to any evident toxicity.…”

Section: A As a Target For Antiviral Therapymentioning

confidence: 99%

“…In fact, several lines of data suggest that this might be the case. Specifically, the S-adenosylhomocysteine (SAC) hydrolase inhibitor 3-deazaadenosine (DAA) has been shown to inhibit m 6 A addition and to act as a broad antiviral inhibitor (57)(58)(59)(60)(61).…”

Section: A As a Target For Antiviral Therapymentioning

confidence: 99%

Viral Epitranscriptomics

Kennedy

Courtney

Tsai

et al. 2017

J Virol

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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. However, recent data generated using HIV-1 as a model system strongly suggest that sites of m 6 A addition not only are evolutionarily conserved but also enhance virus replication. It is therefore likely that the field of viral epitranscriptomics, which can be defined as the study of functionally relevant posttranscriptional modifications of viral RNA transcripts that do not change the nucleotide sequence of that RNA, is poised for a major expansion in scientific interest and may well fundamentally change our understanding of how viral replication is regulated.KEYWORDS Posttranscriptional gene regulation, RNA modification, N 6 -methyladenosine, mRNA function, mRNA stability, HIV-1 W hile over 100 different modified bases have been identified on RNA transcripts in mammalian cells, the majority of these are restricted to noncoding RNAs, especially tRNAs. However, at least 10 distinct modified bases have now been reported to occur in mammalian mRNAs (1). In addition to the 7-methylguanosine cap that is added at the 5= end of all cellular mRNAs, these include N 6 -methyladenosine (m 6 A), 2=-Omethyladenosine (Am), N 6 -2=-O-methyladenosine (m 6 Am), pseudouridine, and 5-methylcytosine. Of these, by far the most prevalent internal modified base found on mRNAs is m 6 A, and recent work has now begun to reveal how m 6 A affects mRNA function and how to precisely map the m 6 A residues present on mRNAs (1-3). m 6 A is also highly prevalent on a wide range of different viral RNA species (4-13), and recently, the first reports demonstrating a significant phenotypic effect of these m 6 A modifications have been published (10-14). Therefore, we will focus this review entirely on m 6 A and how this particular modification might affect different aspects of the viral life cycle. m 6 A was first reported to be present on cellular mRNAs in 1975 with ϳ3 internal m 6 A residues found on the average ϳ2.2-kb transcript (15, 16). However, we now know that many cellular mRNAs, including mRNAs encoding housekeeping genes, lack any m 6 A residues, while highly regulated mRNAs may contain 10 or more (2, 3). The first demonstration of m 6 A residues on viral mRNAs soon followed and, using the biochemical approaches available at that time, a range of mRNAs encoded by several nuclear DNA and RNA viruses were then shown to bear fairly high levels of m 6 A, with the eight influ...

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“…Because DZA is also able to serve as a substrate for Ado-Hcy hydrolase, the interaction between DZA and Ado-Hcy hydrolase results in the accumulation of 3-deazaadenosylhomocysteine (DZAHcy) in cultured cells [2] and the liver [3]. It is also well known that DZA exerts a wide variety of biological functions such as anti-human immunodeficiency virus (HIV) activity [4], anti-inflammatory effects [5], alterations in the expression of genes like collagen IV and ICAM-1 [6,7], the inhibition of TNF-α and IL-1β expression [8], and an inhibitory effect on nuclear NF-κB transcriptional activity [9]. In addition, DZA has been reported to induce apoptosis in human and murine leukemic cell lines such as HL-60, U937 and L1210 cells [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Induction of the Intrinsic Apoptotic Pathway by 3-Deazaadenosine Is Mediated by BAX Activation in HL-60 Cells

Lee

Kang

et al. 2010

Korean J Physiol Pharmacol

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3-Deazaadenosine (DZA), a potent inhibitor of S-adenosylhomocysteine hydrolase, was previously proposed to induce intrinsic apoptosis in human leukemic cells. In the present study, we analyzed the mechanism underlying the DZA-induced intrinsic apoptotic pathway. DZA activated typical caspase-dependent apoptosis in HL-60 cells, as demonstrated by an accumulation of hypo-diploidic cells, the processing of multiple procaspases and an inhibitory effect of z-VAD-Fmk on this cell death. During DZA-induced apoptosis, cytochrome c (cyt c) was released into the cytosol. This was neither prevented by z-VAD-Fmk and nor was it associated with the dissipation of mitochondrial membrane potential (Δ Ψ m). Prior to the release of cyt c, BAX was translocated from the cytosol to mitochondria and underwent oligomerization. Finally, the overexpression of BCL-XL protected HL-60 cells from apoptosis by blocking both the cyt c release and BAX oligomerization. Collectively, these findings suggest that DZA may activate intrinsic apoptosis by stimulating BAX activation and thereby the release of cyt c.

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Anti-human immunodeficiency virus 1 (HIV-1) activities of 3-deazaadenosine analogs: increased potency against 3'-azido-3'-deoxythymidine-resistant HIV-1 strains.

Cited by 62 publications

References 31 publications

Trimethylguanosine capping selectively promotes expression of Rev-dependent HIV-1 RNAs

Trimethylguanosine capping selectively promotes expression of Rev-dependent HIV-1 RNAs

Viral Epitranscriptomics

Induction of the Intrinsic Apoptotic Pathway by 3-Deazaadenosine Is Mediated by BAX Activation in HL-60 Cells

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