scholarly journals Inhibition of off-target cleavage by RNase H using an artificial cationic oligosaccharide

2021 ◽  
Author(s):  
Rintaro Iwata Iwata Hara ◽  
Takeshi Wada
Keyword(s):  
Side Effects ◽  
Antisense Oligonucleotide ◽  
Rnase H ◽  
Ribonuclease H ◽  
Sequence Dependent ◽  
Target Effects

Sequence-dependent off-target effects are a serious problem of antisense oligonucleotide-based drugs. Some of these side effects are induced by ribonuclease H (RNase H)-mediated cleavage of non-target RNAs with similar base...

scholarly journals Antiretroviral Drugs Impact Autophagy with Toxic Outcomes

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 909
Author(s):  
Laura Cheney ◽  
John M. Barbaro ◽  
Joan W. Berman
Keyword(s):  
Quality Control ◽  
Antiretroviral Therapy ◽  
Side Effects ◽  
Viral Suppression ◽  
Antiretroviral Drugs ◽  
People Living With Hiv ◽  
Foreign Material ◽  
Complete Understanding ◽  
Living With Hiv ◽  
Target Effects

Antiretroviral drugs have dramatically improved the morbidity and mortality of people living with HIV (PLWH). While current antiretroviral therapy (ART) regimens are generally well-tolerated, risks for side effects and toxicity remain as PLWH must take life-long medications. Antiretroviral drugs impact autophagy, an intracellular proteolytic process that eliminates debris and foreign material, provides nutrients for metabolism, and performs quality control to maintain cell homeostasis. Toxicity and adverse events associated with antiretrovirals may be due, in part, to their impacts on autophagy. A more complete understanding of the effects on autophagy is essential for developing antiretroviral drugs with decreased off target effects, meaning those unrelated to viral suppression, to minimize toxicity for PLWH. This review summarizes the findings and highlights the gaps in our knowledge of the impacts of antiretroviral drugs on autophagy.

scholarly journals Genetic evidence for two protein domains and a potential new activity in bacteriophage T4 DNA polymerase.

Genetics ◽  
1990 ◽  
Vol 124 (2) ◽  
pp. 213-220 ◽  
Author(s):  
L J Reha-Krantz
Keyword(s):  
Dna Polymerase ◽  
Bacteriophage T4 ◽  
Rnase H ◽  
Ribonuclease H ◽  
Temperature Sensitive ◽  
Polymerase Gene ◽  
Dna Polymerase I ◽  
E Coli ◽  
Intragenic Complementation ◽  
Polymerase I

Abstract Intragenic complementation was detected within the bacteriophage T4 DNA polymerase gene. Complementation was observed between specific amino (N)-terminal, temperature-sensitive (ts) mutator mutants and more carboxy (C)-terminal mutants lacking DNA polymerase polymerizing functions. Protein sequences surrounding N-terminal mutation sites are similar to sequences found in Escherichia coli ribonuclease H (RNase H) and in the 5'----3' exonuclease domain of E. coli DNA polymerase I. These observations suggest that T4 DNA polymerase, like E. coli DNA polymerase I, contains a discrete N-terminal domain.

scholarly journals Hepatitis B virus polymerase restricts LINE-1 retrotransposition

2021 ◽  
Author(s):  
Yasuo Ariumi
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Rna Binding ◽  
Rnase H ◽  
Ribonuclease H ◽  
Independent Manner ◽  
Cytoplasmic Rna ◽  
B Virus ◽  
Long Interspersed Element ◽  
L1 Retrotransposon

Long interspersed element-1 (LINE-1, L1) retrotransposon composes about 17% of the human genome. However, genetic and biochemical interactions between L1 and hepatitis B virus (HBV) remain poorly understood. In this study, we found that HBV restricts L1 mobility without inhibiting the L1 promoter activity. Notably, HBV polymerase (Pol) strongly inhibited L1 retrotransposition in a reverse transcriptase (RT)-independent manner. Indeed, the ribonuclease H (RNase H) domain was essential for inhibition of L1 retrotransposition. L1 ORF1p RNA-binding protein predominantly localized into cytoplasmic RNA granule termed P-body. However, HBV Pol sequestered L1 ORF1p from P-body and colocalized with L1 ORF1p in cytoplasm, when both proteins were co-expressed. Altogether, HBV Pol seems to restrict L1 mobility through a sequestration of L1 ORF1p from P-body. Thus, these results suggest a novel function or activity of HBV Pol in regulation of L1 retrotransposition.

scholarly journals Impact of pharmacological agents on mitochondrial function: a growing opportunity?

2019 ◽  
Vol 47 (6) ◽  
pp. 1757-1772 ◽  
Author(s):  
Megan L. Stoker ◽  
Emma Newport ◽  
James C. Hulit ◽  
A. Phillip West ◽  
Karl J. Morten
Keyword(s):  
Side Effects ◽  
Mitochondrial Function ◽  
Immune Modulation ◽  
Antiviral Agents ◽  
Aging Population ◽  
Drug Induced ◽  
Pharmacological Agents ◽  
Beneficial Effects ◽  
Drug Classes ◽  
Target Effects

Present-day drug therapies provide clear beneficial effects as many diseases can be driven into remission and the symptoms of others can be efficiently managed; however, the success of many drugs is limited due to both patient non-compliance and adverse off-target or toxicity-induced effects. There is emerging evidence that many of these side effects are caused by drug-induced impairment of mitochondrial function and eventual mitochondrial dysfunction. It is imperative to understand how and why drug-induced side effects occur and how mitochondrial function is affected. In an aging population, age-associated drug toxicity is another key area of focus as the majority of patients on medication are older. Therefore, with an aging population possessing subtle or even more dramatic individual differences in mitochondrial function, there is a growing necessity to identify and understand early on potentially significant drug-associated off-target effects and toxicity issues. This will not only reduce the number of unwanted side effects linked to mitochondrial toxicity but also identify useful mitochondrial-modulating agents. Mechanistically, many successful drug classes including diabetic treatments, antibiotics, chemotherapies and antiviral agents have been linked to mitochondrial targeted effects. This is a growing area, with research to repurpose current medications affecting mitochondrial function being assessed in cancer, the immune system and neurodegenerative disorders including Parkinson's disease. Here, we review the effects that pharmacological agents have on mitochondrial function and explore the opportunities from these effects as potential disease treatments. Our focus will be on cancer treatment and immune modulation.

Prediction of the binding mode and resistance profile for a dual-target pyrrolyl diketo acid scaffold against HIV-1 integrase and reverse-transcriptase-associated ribonuclease H

2018 ◽  
Vol 20 (37) ◽  
pp. 23873-23884 ◽  
Author(s):  
Fengyuan Yang ◽  
Guoxun Zheng ◽  
Tingting Fu ◽  
Xiaofeng Li ◽  
Gao Tu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Binding Mode ◽  
Hiv Treatment ◽  
Rnase H ◽  
Ribonuclease H ◽  
Resistance Profile ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Dual Target

The recently developed pyrrolyl diketo acid scaffold targeting both HIV-1 IN and RNase H is beneficial to counteract the failure of anti-HIV treatment due to drug resistance.

scholarly journals Human Cytomegalovirus Mutant with Sequence-Dependent Resistance to the Phosphorothioate Oligonucleotide Fomivirsen (ISIS 2922)

1998 ◽  
Vol 42 (4) ◽  
pp. 971-973 ◽  
Author(s):  
Gilbert B. Mulamba ◽  
André Hu ◽  
Raana F. Azad ◽  
Kevin P. Anderson ◽  
Donald M. Coen
Keyword(s):  
Human Cytomegalovirus ◽  
Antisense Oligonucleotide ◽  
Cross Resistance ◽  
Base Sequence ◽  
Target Sequence ◽  
Phosphorothioate Oligonucleotide ◽  
Sequence Dependent ◽  
Unrelated Sequence

ABSTRACT A human cytomegalovirus mutant that was isolated for resistance (10-fold) to the antisense oligonucleotide fomivirsen (ISIS 2922) exhibited cross-resistance to a modified derivative of fomivirsen with an identical base sequence but little or no resistance to an oligonucleotide with an unrelated sequence. No changes in the mutant’s DNA corresponding to the fomivirsen target sequence were found.

Selective mRNA degradation by antisense oligonucleotide-2,5A chimeras: Involvement of RNase H and RNase L

Biochimie ◽  
1998 ◽  
Vol 80 (8-9) ◽  
pp. 711-720 ◽  
Author(s):  
Ian Robbins ◽  
Guillaume Mitta ◽  
Sylvie Vichier-Guerre ◽  
Robert Sobol ◽  
Anna Ubysz ◽  
...  
Keyword(s):  
Antisense Oligonucleotide ◽  
Mrna Degradation ◽  
Rnase H ◽  
Rnase L

scholarly journals 3-Hydroxypyrimidine-2,4-Diones as Novel Hepatitis B Virus Antivirals Targeting the Viral Ribonuclease H

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Andrew D. Huber ◽  
Eleftherios Michailidis ◽  
Jing Tang ◽  
Maritza N. Puray-Chavez ◽  
Maria Boftsi ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Antiviral Activity ◽  
Essential Role ◽  
Rnase H ◽  
Ribonuclease H ◽  
Hbv Replication ◽  
B Virus ◽  
Infected Cells ◽  
Micromolar Range

ABSTRACT Hepatitis B virus (HBV) RNase H (RNH) is an appealing therapeutic target due to its essential role in viral replication. RNH inhibitors (RNHIs) could help to more effectively control HBV infections. Here, we report 3-hydroxypyrimidine-2,4-diones as novel HBV RNHIs with antiviral activity. We synthesized and tested 52 analogs and found 4 that inhibit HBV RNH activity in infected cells. Importantly, 2 of these compounds inhibited HBV replication in the low micromolar range.

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