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Viruses
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Viral Nucleases
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Viral Nucleases

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 12224

Special Issue Editors

Prof. Dr. Zhengqiang Wang

E-Mail Website
Guest Editor
Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA
Interests: Antiviral drug design; HIV-1; human cytomegalovirus (HCMV); hepatitis B virus (HBV); emerging viruses
Prof. Dr. Robert J. Geraghty

E-Mail Website
Guest Editor
Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA
Interests: herpesvirus genome packaging; flavivirus and coronavirus gene expression and genome replication; human cytomegalovirus; Zika virus; dengue virus; SARS-CoV-2; antiviral inhibitor identication;

Special Issue Information

Dear Colleagues,

We are organizing a Special Issue in Viruses to stimulate interest in and reporting of research targeting viral nucleases. Nucleases are ubiquitous hydrolytic enzymes that cleave the phosphodiester bond between nucleotides, within the strand (endonucleases) or from the end (as in exonucleases). With diverse active site structures and catalytic mechanisms, nucleases play a wide range of essential roles in viral replication and virus–host interactions. Key nuclease functions include genome replication (HIV and HBV RNase H), cap-snatching (influenza virus PA endonuclease), genome packaging (herpesvirus terminase endonuclease), proof-reading (SARS-CoV-2 NSP14 ExoN), and innate immune evasion (SARS-CoV-2 NSP15 EndoU). Although the successful development of the endonuclease-targeting baloxavir as an influenza drug provides a clinical validation for viral nucleases as potential antiviral targets, many of these nuclease functions remain underexplored in antiviral research.

We welcome manuscripts describing the virology, structural biology, biochemistry, medicinal chemistry, and pharmacology of any viral nucleases and inhibitors thereof, including but not limited to the abovementioned RNA and DNA, endo- and exonucleases, via metal-dependent or metal-independent catalytic mechanisms. Manuscripts of both original research and reviews are encouraged. The intention to contribute review articles must be communicated to the guest editors for preliminary topic consideration. 

Prof. Dr. Zhengqiang Wang
Prof. Dr. Robert J. Geraghty
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • endonuclease
  • exonuclease
  • inhibitors
  • medicinal chemistry
  • virology
  • biochemistry
  • structural biology
  • pharmacology
  • antiviral

Published Papers (5 papers)

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Editorial

Jump to: Research, Review

2 pages, 197 KiB  
Editorial
Viral Nucleases
by Zhengqiang Wang and Robert J. Geraghty
Viruses 2023, 15(3), 740; https://doi.org/10.3390/v15030740 - 13 Mar 2023
Viewed by 1000
Abstract
Nucleases are ubiquitous hydrolytic enzymes that cleave phosphodiester bond of DNA (DNases), RNA (RNases), or protein-RNA/DNA (phosphodiesterases), within the strand (endonucleases) or from the end (exonucleases) [...] Full article
(This article belongs to the Special Issue Viral Nucleases)

Research

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9 pages, 5869 KiB  
Article
SARS-CoV-2 nsp14 Exoribonuclease Removes the Natural Antiviral 3′-Deoxy-3′,4′-didehydro-cytidine Nucleotide from RNA
by Nicholas H. Moeller, Kellan T. Passow, Daniel A. Harki and Hideki Aihara
Viruses 2022, 14(8), 1790; https://doi.org/10.3390/v14081790 - 16 Aug 2022
Cited by 6 | Viewed by 2024
Abstract
The on-going global pandemic of COVID-19 is caused by SARS-CoV-2, which features a proofreading mechanism to facilitate the replication of its large RNA genome. The 3′-to-5′ exoribonuclease (ExoN) activity of SARS-CoV-2 non-structural protein 14 (nsp14) removes nucleotides misincorporated during RNA synthesis by the [...] Read more.
The on-going global pandemic of COVID-19 is caused by SARS-CoV-2, which features a proofreading mechanism to facilitate the replication of its large RNA genome. The 3′-to-5′ exoribonuclease (ExoN) activity of SARS-CoV-2 non-structural protein 14 (nsp14) removes nucleotides misincorporated during RNA synthesis by the low-fidelity viral RNA-dependent RNA polymerase (RdRp) and thereby compromises the efficacy of antiviral nucleoside/nucleotide analogues. Here we show biochemically that SARS-CoV-2 nsp14 can excise the natural antiviral chain-terminating nucleotide, 3′-deoxy-3′,4′-didehydro-cytidine 5′-monophosphate (ddhCMP), incorporated by RdRp at the 3′ end of an RNA strand. Nsp14 ExoN processes an RNA strand terminated with ddhCMP more efficiently than that with a non-physiological chain terminator 3′-deoxy-cytidine monophosphate (3′-dCMP), whereas RdRp is more susceptible to chain termination by 3′-dCTP than ddhCTP. These results suggest that nsp14 ExoN could play a role in protecting SARS-CoV-2 from ddhCTP, which is produced as part of the innate immune response against viral infections, and that the SARS-CoV-2 enzymes may have adapted to minimize the antiviral effect of ddhCTP. Full article
(This article belongs to the Special Issue Viral Nucleases)
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17 pages, 4118 KiB  
Article
Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones
by Otávio Augusto Chaves, Natalia Fintelman-Rodrigues, Xuanting Wang, Carolina Q. Sacramento, Jairo R. Temerozo, André C. Ferreira, Mayara Mattos, Filipe Pereira-Dutra, Patrícia T. Bozza, Hugo Caire Castro-Faria-Neto, James J. Russo, Jingyue Ju and Thiago Moreno L. Souza
Viruses 2022, 14(7), 1458; https://doi.org/10.3390/v14071458 - 30 Jun 2022
Cited by 26 | Viewed by 3182
Abstract
Despite the fast development of vaccines, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still circulating and generating variants of concern (VoC) that escape the humoral immune response. In this context, the search for anti-SARS-CoV-2 compounds is still essential. A class of natural [...] Read more.
Despite the fast development of vaccines, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still circulating and generating variants of concern (VoC) that escape the humoral immune response. In this context, the search for anti-SARS-CoV-2 compounds is still essential. A class of natural polyphenols known as flavonoids, frequently available in fruits and vegetables, is widely explored in the treatment of different diseases and used as a scaffold for the design of novel drugs. Therefore, herein we evaluate seven flavonoids divided into three subclasses, isoflavone (genistein), flavone (apigenin and luteolin) and flavonol (fisetin, kaempferol, myricetin, and quercetin), for COVID-19 treatment using cell-based assays and in silico calculations validated with experimental enzymatic data. The flavonols were better SARS-CoV-2 inhibitors than isoflavone and flavones. The increasing number of hydroxyl groups in ring B of the flavonols kaempferol, quercetin, and myricetin decreased the 50% effective concentration (EC50) value due to their impact on the orientation of the compounds inside the target. Myricetin and fisetin appear to be preferred candidates; they are both anti-inflammatory (decreasing TNF-α levels) and inhibit SARS-CoV-2 mainly by targeting the processability of the main protease (Mpro) in a non-competitive manner, with a potency comparable to the repurposed drug atazanavir. However, fisetin and myricetin might also be considered hits that are amenable to synthetic modification to improve their anti-SARS-CoV-2 profile by inhibiting not only Mpro, but also the 3′–5′ exonuclease (ExoN). Full article
(This article belongs to the Special Issue Viral Nucleases)
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15 pages, 3051 KiB  
Article
Identifying Structural Features of Nucleotide Analogues to Overcome SARS-CoV-2 Exonuclease Activity
by Xuanting Wang, Chuanjuan Tao, Irina Morozova, Sergey Kalachikov, Xiaoxu Li, Shiv Kumar, James J. Russo and Jingyue Ju
Viruses 2022, 14(7), 1413; https://doi.org/10.3390/v14071413 - 28 Jun 2022
Cited by 4 | Viewed by 2658
Abstract
With the recent global spread of new SARS-CoV-2 variants, there remains an urgent need to develop effective and variant-resistant oral drugs. Recently, we reported in vitro results validating the use of combination drugs targeting both the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and proofreading [...] Read more.
With the recent global spread of new SARS-CoV-2 variants, there remains an urgent need to develop effective and variant-resistant oral drugs. Recently, we reported in vitro results validating the use of combination drugs targeting both the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and proofreading exonuclease (ExoN) as potential COVID-19 therapeutics. For the nucleotide analogues to be efficient SARS-CoV-2 inhibitors, two properties are required: efficient incorporation by RdRp and substantial resistance to excision by ExoN. Here, we have selected and evaluated nucleotide analogues with a variety of structural features for resistance to ExoN removal when they are attached at the 3′ RNA terminus. We found that dideoxynucleotides and other nucleotides lacking both 2′- and 3′-OH groups were most resistant to ExoN excision, whereas those possessing both 2′- and 3′-OH groups were efficiently removed. We also found that the 3′-OH group in the nucleotide analogues was more critical than the 2′-OH for excision by ExoN. Since the functionally important sequences in Nsp14/10 are highly conserved among all SARS-CoV-2 variants, these identified structural features of nucleotide analogues offer invaluable insights for designing effective RdRp inhibitors that can be simultaneously efficiently incorporated by the RdRp and substantially resist ExoN excision. Such newly developed RdRp terminators would be good candidates to evaluate their ability to inhibit SARS-CoV-2 in cell culture and animal models, perhaps combined with additional exonuclease inhibitors to increase their overall effectiveness. Full article
(This article belongs to the Special Issue Viral Nucleases)
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Review

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22 pages, 6740 KiB  
Review
Viral Nucleases from Herpesviruses and Coronavirus in Recombination and Proofreading: Potential Targets for Antiviral Drug Discovery
by Lee R. Wright, Dennis L. Wright and Sandra K. Weller
Viruses 2022, 14(7), 1557; https://doi.org/10.3390/v14071557 - 16 Jul 2022
Cited by 1 | Viewed by 2543
Abstract
In this review, we explore recombination in two very different virus families that have become major threats to human health. The Herpesviridae are a large family of pathogenic double-stranded DNA viruses involved in a range of diseases affecting both people and animals. Coronaviridae [...] Read more.
In this review, we explore recombination in two very different virus families that have become major threats to human health. The Herpesviridae are a large family of pathogenic double-stranded DNA viruses involved in a range of diseases affecting both people and animals. Coronaviridae are positive-strand RNA viruses (CoVs) that have also become major threats to global health and economic stability, especially in the last two decades. Despite many differences, such as the make-up of their genetic material (DNA vs. RNA) and overall mechanisms of genome replication, both human herpes viruses (HHVs) and CoVs have evolved to rely heavily on recombination for viral genome replication, adaptation to new hosts and evasion of host immune regulation. In this review, we will focus on the roles of three viral exonucleases: two HHV exonucleases (alkaline nuclease and PolExo) and one CoV exonuclease (ExoN). We will review the roles of these three nucleases in their respective life cycles and discuss the state of drug discovery efforts against these targets. Full article
(This article belongs to the Special Issue Viral Nucleases)
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