scholarly journals Histone Deacetylase Inhibitors as Potential COVID-19 Virus RNA-Dependent RNA Polymerase Inhibitors: A Molecular Docking and Dynamics Study

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Mohamed MFA ◽  
◽  
Sayed AM ◽  
Abdelmohsen UR ◽  
Nafady A ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Structural Characteristics ◽  
Hdac Inhibitors ◽  
Viral Rna ◽  
Crystallographic Structure ◽  
Rna Dependent Rna Polymerase ◽  
Structure Based Drug Design ◽  
Health Crisis

The novel coronavirus disease that initially appeared in 2019, commonly identified as COVID-19 is an acute infectious disease precipitated by the SARSCoV- 2 and has become a severe pandemic health crisis. People stricken with a severe case of COVID-19 are subject to a relatively higher mortality rate, which is brought about predominantly by the difficulty of having potent and specific antiviral drugs for its treatment. In this context, the viral RNA-dependent RNA polymerase (RdRp) is an attractive target for antiviral inhibitors, mainly because of its essential role in processing the polyproteins translated from viral RNA. Moreover, histone deacetylases inhibitors represent one of the most promising antiviral agents. Therefore, in this contribution, the in silico structure-based drug design approach was employed to identify novel structural characteristics for the potential repurposed activity of HDACIs as antivirals against COVID-19. Herein, 12 HDAC inhibitors were screened to explore their potential anti-viral activity against RNA-dependent RNA polymerase (RdRp) (6NUR). Results revealed that large number of the screened HDAC inhibitors are strongly bound into the active binding site of crystallographic structure of RNA-dependent RNA polymerase (RdRp) (6NUR) with lowest CDOCKER energy and CDOCKER interaction energy are very close to those of the control drug remdesivir. Importantly, the virtually screened HDAC inhibitors, particularly, Givinostat, Pracinostat, Panobinostat, Romidepsin (FK228) and its active metabolite (RedF) could be promising candidates for COVID-19 RNA-dependent RNA polymerase (RdRp) inhibitors. Significantly, these inhibitors should be evaluated on their effectivity when treating COVID-19, specifically using the drugs that have been approved for clinical trials with limited toxicity.

Discovery of Potent Non-Nucleoside Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase from a Fragment Hit Using Structure-Based Drug Design

2016 ◽  
Vol 59 (8) ◽  
pp. 3935-3952 ◽  
Author(s):  
Fumiaki Yokokawa ◽  
Shahul Nilar ◽  
Christian G. Noble ◽  
Siew Pheng Lim ◽  
Ranga Rao ◽  
...  
Keyword(s):  
Drug Design ◽  
Rna Polymerase ◽  
Viral Rna ◽  
Rna Dependent Rna Polymerase ◽  
Structure Based Drug Design ◽  
Nucleoside Inhibitors

scholarly journals Zinc Salts Block Hepatitis E Virus Replication by Inhibiting the Activity of Viral RNA-Dependent RNA Polymerase

2017 ◽  
Vol 91 (21) ◽  
Author(s):  
Nidhi Kaushik ◽  
Chandru Subramani ◽  
Saumya Anang ◽  
Rajagopalan Muthumohan ◽  
Shalimar ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Hepatitis E Virus ◽  
Zinc Supplementation ◽  
Hepatitis E ◽  
Viral Rna ◽  
Health Concern ◽  
Healthy Individuals ◽  
Genomic Rna ◽  
Rna Dependent Rna Polymerase ◽  
Zinc Salts

ABSTRACT Hepatitis E virus (HEV) causes an acute, self-limiting hepatitis in healthy individuals and leads to chronic disease in immunocompromised individuals. HEV infection in pregnant women results in a more severe outcome, with the mortality rate going up to 30%. Though the virus usually causes sporadic infection, epidemics have been reported in developing and resource-starved countries. No specific antiviral exists against HEV. A combination of interferon and ribavirin therapy has been used to control the disease with some success. Zinc is an essential micronutrient that plays crucial roles in multiple cellular processes. Zinc salts are known to be effective in reducing infections caused by few viruses. Here, we investigated the effect of zinc salts on HEV replication. In a human hepatoma cell (Huh7) culture model, zinc salts inhibited the replication of genotype 1 (g-1) and g-3 HEV replicons and g-1 HEV infectious genomic RNA in a dose-dependent manner. Analysis of a replication-defective mutant of g-1 HEV genomic RNA under similar conditions ruled out the possibility of zinc salts acting on replication-independent processes. An ORF4-Huh7 cell line-based infection model of g-1 HEV further confirmed the above observations. Zinc salts did not show any effect on the entry of g-1 HEV into the host cell. Furthermore, our data reveal that zinc salts directly inhibit the activity of viral RNA-dependent RNA polymerase (RdRp), leading to inhibition of viral replication. Taken together, these studies unravel the ability of zinc salts in inhibiting HEV replication, suggesting their possible therapeutic value in controlling HEV infection. IMPORTANCE Hepatitis E virus (HEV) is a public health concern in resource-starved countries due to frequent outbreaks. It is also emerging as a health concern in developed countries owing to its ability to cause acute and chronic infection in organ transplant and immunocompromised individuals. Although antivirals such as ribavirin have been used to treat HEV cases, there are known side effects and limitations of such therapy. Our discovery of the ability of zinc salts to block HEV replication by virtue of their ability to inhibit the activity of viral RdRp is important because these findings pave the way to test the efficacy of zinc supplementation therapy in HEV-infected patients. Since zinc supplementation therapy is known to be safe in healthy individuals and since high-dose zinc is used in the treatment of Wilson's disease, it may be possible to control HEV-associated health problems following a similar treatment regimen.

Histone deacetylase inhibitors and their potential role in inflammatory bowel diseases

2011 ◽  
Vol 39 (4) ◽  
pp. 1092-1095 ◽  
Author(s):  
Alexander J.P. Edwards ◽  
Sylvia L.F. Pender
Keyword(s):  
Gene Transcription ◽  
Inflammatory Bowel Diseases ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
T Regulatory Cells ◽  
Hdac Inhibitors ◽  
Novel Treatments ◽  
Bowel Diseases ◽  
Normal Gene ◽  
Inflammatory Bowel

IBDs (inflammatory bowel diseases) are lifelong manifestations that significantly impair the quality of life of those who suffer from them. Although many therapies are now available, including immunomodulatory drugs such as Infliximab which have efficacy in IBD, not all patients respond and some patients generate autoantibodies against these drugs. Hence the search for novel treatments is ongoing. HDACs (histone deacetylases) are responsible for condensation of chromatin in the nucleus of cells and inhibition of gene transcription and are often dysregulated during cancer. HDAC inhibitors allow normal gene transcription to be restored and provide attractive therapeutic options, as they have been shown to be anti-inflammatory and anti-proliferative in cancer. Indeed, two HDAC inhibitors have been recently approved for the treatment of cutaneous T-cell lymphoma in the U.S.A. Recent research using animal models has shown that HDAC inhibitors may have a beneficial effect in colitis by boosting levels of Foxp3+ (forkhead box P3+) T-regulatory cells that dampen inflammation. In the present paper, we outline the background to IBD, HDACs and their inhibitors as well as discussing their current use in models of IBD.

scholarly journals Spatial Perturbations within an RNA Promoter Specifically Recognized by a Viral RNA-Dependent RNA Polymerase (RdRp) Reveal That RdRp Can Adjust Its Promoter Binding Sites

1999 ◽  
Vol 73 (1) ◽  
pp. 198-204 ◽  
Author(s):  
Scott Stevenson Stawicki ◽  
C. Cheng Kao
Keyword(s):  
Rna Polymerase ◽  
Rna Synthesis ◽  
Core Promoter ◽  
Brome Mosaic Virus ◽  
Viral Rna ◽  
Rna Dependent Rna Polymerase ◽  
Dna And Rna ◽  
In The Wild ◽  
Nucleotide Insertions

ABSTRACT RNA synthesis during viral replication requires specific recognition of RNA promoters by the viral RNA-dependent RNA polymerase (RdRp). Four nucleotides (−17, −14, −13, and −11) within the brome mosaic virus (BMV) subgenomic core promoter are required for RNA synthesis by the BMV RdRp (R. W. Siegel et al., Proc. Natl. Acad. Sci. USA 94:11238–11243, 1997). The spatial requirements for these four nucleotides and the initiation (+1) cytidylate were examined in RNAs containing nucleotide insertions and deletions within the BMV subgenomic core promoter. Spatial perturbations between nucleotides −17 and −11 resulted in decreased RNA synthesis in vitro. However, synthesis was still dependent on the key nucleotides identified in the wild-type core promoter and the initiation cytidylate. In contrast, changes between nucleotides −11 and +1 had a less severe effect on RNA synthesis but resulted in RNA products initiated at alternative locations in addition to the +1 cytidylate. The results suggest a degree of flexibility in the recognition of the subgenomic promoter by the BMV RdRp and are compared with functional regions in other DNA and RNA promoters.

scholarly journals (F)uridylylated Peptides Linked to VPg1 of Foot-and- Mouth Disease Virus (FMDV): Design, Synthesis and X-Ray Crystallography of the Complexes with FMDV RNA-Dependent RNA Polymerase

Molecules ◽  
2019 ◽  
Vol 24 (13) ◽  
pp. 2360 ◽  
Author(s):  
Sonia de Castro ◽  
Cristina Ferrer-Orta ◽  
Alberto Mills ◽  
Gloria Fernández-Cureses ◽  
Federico Gago ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Disease Virus ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Viral Rna ◽  
Hydroxyl Group ◽  
Rna Dependent Rna Polymerase ◽  
X Ray ◽  
Mouth Disease Virus ◽  
Foot And Mouth

Foot-and-mouth disease virus (FMDV) is an RNA virus belonging to the Picornaviridae family that contains three small viral proteins (VPgs), named VPg1, VPg2 and VPg3, linked to the 5′-end of the viral genome. These VPg proteins act as primers for RNA replication, which is initiated by the consecutive binding of two UMP molecules to the hydroxyl group of Tyr3 in VPg. This process, termed uridylylation, is catalyzed by the viral RNA-dependent RNA polymerase named 3Dpol. 5-Fluorouridine triphosphate (FUTP) is a potent competitive inhibitor of VPg uridylylation. Peptide analysis showed FUMP covalently linked to the Tyr3 of VPg. This fluorouridylylation prevents further incorporation of the second UMP residue. The molecular basis of how the incorporated FUMP blocks the incorporation of the second UMP is still unknown. To investigate the mechanism of inhibition of VPg uridylylation by FUMP, we have prepared a simplified 15-mer model of VPg1 containing FUMP and studied its x-ray crystal structure in complex with 3Dpol. Unfortunately, the fluorouridylylated VPg1 was disordered and not visible in the electron density maps; however, the structure of 3Dpol in the presence of VPg1-FUMP showed an 8 Å movement of the β9-α11 loop of the polymerase towards the active site cavity relative to the complex of 3Dpol with VPg1-UMP. The conformational rearrangement of this loop preceding the 3Dpol B motif seems to block the access of the template nucleotide to the catalytic cavity. This result may be useful in the design of new antivirals against not only FMDV but also other picornaviruses, since all members of this family require the uridylylation of their VPg proteins to initiate the viral RNA synthesis.

scholarly journals Sequences at the 3′ Untranslated Region of Bamboo Mosaic Potexvirus RNA Interact with the Viral RNA-Dependent RNA Polymerase

2001 ◽  
Vol 75 (6) ◽  
pp. 2818-2824 ◽  
Author(s):  
Cheng-Yen Huang ◽  
Yih-Leh Huang ◽  
Menghsiao Meng ◽  
Yau-Heiu Hsu ◽  
Ching-Hsiu Tsai
Keyword(s):  
Rna Polymerase ◽  
Untranslated Region ◽  
Rna Binding ◽  
Bovine Liver ◽  
Viral Rna ◽  
Mobility Shift ◽  
Rna Dependent Rna Polymerase ◽  
Stem Loop ◽  
Competition Analysis ◽  
Reading Frame

ABSTRACT The 3′ untranslated region (UTR) of bamboo mosaic potexvirus (BaMV) genomic RNA was found to fold into a series of stem-loop structures including a pseudoknot structure. These structures were demonstrated to be important for viral RNA replication and were believed to be recognized by the replicase (C.-P. Cheng and C.-H. Tsai, J. Mol. Biol. 288:555–565, 1999). Electrophoretic mobility shift and competition assays have now been used to demonstrate that theEscherichia coli-expressed RNA-dependent RNA polymerase domain (Δ893) derived from BaMV open reading frame 1 could specifically bind to the 3′ UTR of BaMV RNA. No competition was observed when bovine liver tRNAs or poly(I)(C) double-stranded homopolymers were used as competitors, and the cucumber mosaic virus 3′ UTR was a less efficient competitor. Competition analysis with different regions of the BaMV 3′ UTR showed that Δ893 binds to at least two independent RNA binding sites, stem-loop D and the poly(A) tail. Footprinting analysis revealed that Δ893 could protect the sequences at loop D containing the potexviral conserved hexamer motif and part of the stem of domain D from chemical cleavage.

scholarly journals Cytoplasmic Viral RNA-Dependent RNA Polymerase Disrupts the Intracellular Splicing Machinery by Entering the Nucleus and Interfering with Prp8

2014 ◽  
Vol 10 (6) ◽  
pp. e1004199 ◽  
Author(s):  
Yen-Chin Liu ◽  
Rei-Lin Kuo ◽  
Jing-Yi Lin ◽  
Peng-Nien Huang ◽  
Yi Huang ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Viral Rna ◽  
Rna Dependent Rna Polymerase ◽  
Splicing Machinery

A pyrazolotriazolopyrimidinamine inhibitor of bovine viral diarrhea virus replication that targets the viral RNA-dependent RNA polymerase

2009 ◽  
Vol 82 (3) ◽  
pp. 141-147 ◽  
Author(s):  
Jan Paeshuyse ◽  
Carine Letellier ◽  
Matheus Froeyen ◽  
Hélène Dutartre ◽  
Robert Vrancken ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Virus Replication ◽  
Bovine Viral Diarrhea Virus ◽  
Viral Rna ◽  
Bovine Viral Diarrhea ◽  
Rna Dependent Rna Polymerase ◽  
Diarrhea Virus ◽  
Viral Diarrhea ◽  
Viral Diarrhea Virus
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