RNase H: Specificity, Mechanisms of Action, and Antiviral Target

Moelling, Karin; Broecker, Felix; Kerrigan, John E.

doi:10.1007/978-1-62703-670-2_7

Cited by 9 publications

(9 citation statements)

References 46 publications

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“…RNA‐dependent RNA polymerases (RdRp) are very ancient enzymes and crucial players for all viruses with RNA genomes . Together with reverse transcriptase and various RNases they promote and maintain RNA networks, and are essential agents in key cellular processes, including generating DNA sequences, a basic requirement for cellular life . The reverse transcriptases are also closely related to those of the group II introns—but lacking the intronic RNA sequence structure—as well as being associated with a type of CRISPR/Cas system .…”

Section: Viruses and Their Relativesmentioning

confidence: 99%

“…108 Together with reverse transcriptase and various RNases they promote and maintain RNA networks, and are essential agents in key cellular processes, including generating DNA sequences, a basic requirement for cellular life. 109 The reverse transcriptases are also closely related to those of the group II introns-but lacking the intronic RNA sequence structure-as well as being associated with a type of CRISPR/Cas system. 110 The CRISPR/Cas system is an effective prokaryotic adaptive immune system descended from mobile genetic elements and most likely represents an exapted T/A module, as presented above.…”

Section: Viruses and Their Relativesmentioning

confidence: 99%

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That is life: communicating RNA networks from viruses and cells in continuous interaction

Villarreal

Witzany²

2019

Annals of the New York Academy of Sciences

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All the conserved detailed results of evolution stored in DNA must be read, transcribed, and translated via an RNA‐mediated process. This is required for the development and growth of each individual cell. Thus, all known living organisms fundamentally depend on these RNA‐mediated processes. In most cases, they are interconnected with other RNAs and their associated protein complexes and function in a strictly coordinated hierarchy of temporal and spatial steps (i.e., an RNA network). Clearly, all cellular life as we know it could not function without these key agents of DNA replication, namely rRNA, tRNA, and mRNA. Thus, any definition of life that lacks RNA functions and their networks misses an essential requirement for RNA agents that inherently regulate and coordinate (communicate to) cells, tissues, organs, and organisms. The precellular evolution of RNAs occurred at the core of the emergence of cellular life and the question remained of how both precellular and cellular levels are interconnected historically and functionally. RNA networks and RNA communication can interconnect these levels. With the reemergence of virology in evolution, it became clear that communicating viruses and subviral infectious genetic parasites are bridging these two levels by invading, integrating, coadapting, exapting, and recombining constituent parts in host genomes for cellular requirements in gene regulation and coordination aims. Therefore, a 21st century understanding of life is of an inherently social process based on communicating RNA networks, in which viruses and cells continuously interact.

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Section: Viruses and Their Relativesmentioning

confidence: 99%

Section: Viruses and Their Relativesmentioning

confidence: 99%

That is life: communicating RNA networks from viruses and cells in continuous interaction

Villarreal

Witzany²

2019

Annals of the New York Academy of Sciences

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“…At least seven different nucleoside RT inhibitors (NRTIs), one nucleotide RT inhibitor (NtRTI), and five non-nucleoside RT inhibitors (NNRTIs) of HIV-1 RT have been formally approved for clinical use . In addition, several non-nucleoside-competing RT inhibitors (NcRTIs) and RNase H inhibitors have been discovered that act against HIV-1 RT in a manner that is structurally and functionally different from that of N(t)RTIs and NNRTIs. − With regard to herpesvirus therapy, a variety of structurally distinct inhibitors of herpetic DNA polymerases have been reported, and several of them are clinically used . The best known examples are the acyclic nucleoside analogues acyclovir and its oral prodrug valacyclovir, penciclovir and its prodrug famciclovir, and ganciclovir and its prodrug valganciclovir .…”

Section: Introductionmentioning

confidence: 99%

Pronounced Inhibition Shift from HIV Reverse Transcriptase to Herpetic DNA Polymerases by Increasing the Flexibility of α-Carboxy Nucleoside Phosphonates

John¹,

Kim²,

Bennett

et al. 2015

J. Med. Chem.

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Alpha-carboxynucleoside phosphonates (α-CNPs) are novel viral DNA polymerase inhibitors that do not need metabolic conversion for enzyme inhibition. The prototype contains a cyclopentyl linker between nucleobase and α-carboxyphosphonate and preferentially (50- to 100-fold) inhibits HIV-1 RT compared with herpetic DNA polymerases. A synthetic methodology involving three steps has been developed for the synthesis of a series of novel α-CNPs, including a Rh(II) catalyzed O-H insertion which connects the carboxyphosphonate group to a linker moiety and attachment of a nucleobase to the other end of the linker by a Mitsunobu reaction followed by final deprotection. Replacing the cyclopentyl moiety in the prototype α-CNPs by a more flexible entity results in a selectivity shift of ~ 100-fold in favor of the herpetic DNA polymerases when compared to HIV-1 RT. The nature of the kinetic interaction of the acyclic α-CNPs against the herpetic DNA polymerases differs from the nature of the nucleobase-specific kinetic interaction of the cyclopentyl α-CNPs against HIV RT.

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“…Finally, we tested RNase H. RNase H is a particular member of RNases family, which specifically hydrolyzes the RNA strand of RNA:DNA hybrid, playing a critical role in several cellular processes including DNA replication, DNA repair and transcription 1 28 29 . Moreover, as a highly conserved damage repair protein, RNase H can cleave RNA-DNA junctions in Okazaki fragment, processing through its junction ribonuclease (JRNase) activity 30 .…”

mentioning

confidence: 99%

“…Since RNase H has been found to be associated with retroviral reverse transcriptase (e.g., in Human Immunodeficiency Virus, Hepadnaviruses, murine leukemia virus, etc. ), it is becoming a new potential target for viral inhibitors, representing an exciting possibility for developing new anti-viral therapeutics 28 31 32 33 34 . We tested the potential of our approach for the screening and testing of new anti-viral drugs.…”

mentioning

confidence: 99%

A hybrid chimeric system for versatile and ultra-sensitive RNase detection

Persano

Vecchio

Pompa

2015

Sci Rep

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We developed a new versatile strategy that allows the detection of several classes of RNases (i.e., targeting ss- or ds-RNA, DNA/RNA hetero-hybrid or junctions) with higher sensitivity than existing assays. Our two-step approach consists of a DNA-RNA-DNA chimeric Hairpin Probe (cHP) conjugated to magnetic microparticles and containing a DNAzyme sequence in its terminal region, and molecular beacons for fluorescence signal generation. In the first step, the digestion of the RNA portion of the cHP sequences in presence of RNases leads to the release of multiple copies of the DNAzyme in solution. Then, after magnetic washing, each DNAzyme molecule elicits the catalytic cleavage of numerous molecular beacons, providing a strong amplification of the overall sensitivity of the assay. We successfully applied our approach to detect very low concentrations of RNase A, E. coli RNase I, and RNase H. Furthermore, we analyzed the effect of two antibiotics (penicillin and streptomycin) on RNase H activity, demonstrating the applicability of our strategy for the screening of inhibitors. Finally, we exploited our system to detect RNase activity directly in crude biological samples (i.e., blood and saliva) and in cell culture medium, highlighting its suitability as cheap and sensitive tool for the detection of RNase levels.

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RNase H: Specificity, Mechanisms of Action, and Antiviral Target

Cited by 9 publications

References 46 publications

That is life: communicating RNA networks from viruses and cells in continuous interaction

That is life: communicating RNA networks from viruses and cells in continuous interaction

Pronounced Inhibition Shift from HIV Reverse Transcriptase to Herpetic DNA Polymerases by Increasing the Flexibility of α-Carboxy Nucleoside Phosphonates

A hybrid chimeric system for versatile and ultra-sensitive RNase detection

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