Two-Metal Ion-Dependent Enzymes as Potential Antiviral Targets in Human Herpesviruses

DiScipio, Katherine A.; Weerasooriya, Savithri; Szczepaniak, Renata; Hazeen, Akram; Wright, Lee R; Wright, Dennis L.; Weller, Sandra K.

doi:10.1128/mbio.03226-21

Cited by 8 publications

(7 citation statements)

References 90 publications

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“…Several pieces of evidence have demonstrated that metaldependent enzymes are important targets for antiviral discovery (Carcelli et al, 2017;DiScipio et al, 2022). The chelation of metal-ion cofactors is therefore an interesting and approved strategy for the development of novel antiviral therapies (Rogolino et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Inhibition ofArenaviridaenucleoprotein exonuclease by bisphosphonate

Nguyen¹,

Yekwa²,

Selisko³

et al. 2022

Int Union Crystallogr J

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Arenaviruses are emerging enveloped negative-sense RNA viruses that cause neurological and hemorrhagic diseases in humans. Currently, no FDA-approved vaccine or therapeutic agent is available except for ribavirin, which must be administered early during infection for optimum efficacy. A hallmark of arenavirus infection is rapid and efficient immune suppression mediated by the exonuclease domain encoded by the nucleoprotein. This exonuclease is therefore an attractive target for the design of novel antiviral drugs since exonuclease inhibitors might not only have a direct effect on the enzyme but could also boost viral clearance through stimulation of the innate immune system of the host cell. Here, in silico screening and an enzymatic assay were used to identify a novel, specific but weak inhibitor of the arenavirus exonuclease, with IC50 values of 65.9 and 68.6 µM for Mopeia virus and Lymphocytic choriomeningitis virus, respectively. This finding was further characterized using crystallographic and docking approaches. This study serves as a proof of concept and may have assigned a new therapeutic purpose for the bisphosphonate family, therefore paving the way for the development of inhibitors against Arenaviridae.

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Section: Discussionmentioning

confidence: 99%

Inhibition ofArenaviridaenucleoprotein exonuclease by bisphosphonate

Nguyen¹,

Yekwa²,

Selisko³

et al. 2022

Int Union Crystallogr J

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“…This screen identified several hits in the low micromolar range, such as purpurogallin and compound 2 ( Figure 5 ); however, these inhibitors are considered promiscuous metal-chelating agents with low selectivity, making them unattractive for further development. In a parallel effort, we created a privileged library of 250 compounds containing (a) known TMID-directed drug inhibitors of HIV integrase and influenza endoribonuclease, (b) compounds reported to inhibit TMID enzymes (tropolones) and (c) compounds predicted by flexible docking to bind to the active site of the KSHV SOX protein [ 183 ]. These compounds were screened for anti-nuclease activity against several known and potential TMID enzymes [ 183 ].…”

Section: Exonuclease Enzymes Of Hhvmentioning

confidence: 99%

“…In a parallel effort, we created a privileged library of 250 compounds containing (a) known TMID-directed drug inhibitors of HIV integrase and influenza endoribonuclease, (b) compounds reported to inhibit TMID enzymes (tropolones) and (c) compounds predicted by flexible docking to bind to the active site of the KSHV SOX protein [ 183 ]. These compounds were screened for anti-nuclease activity against several known and potential TMID enzymes [ 183 ]. The results of the enzyme inhibition assays were correlated with antiviral activity.…”

Section: Exonuclease Enzymes Of Hhvmentioning

confidence: 99%

“…The strongly antiviral HQ compounds were potent inhibitors of AN with no discernable activity against PolExo. HQ-166 also inhibited viral DNA synthesis and replication compartment formation [ 183 ]. Furthermore, HQ-166 did not show antiviral activity against other viruses (including adeno, chikungunya, dengue, influenza and zika), indicating specificity for herpesvirus replication (NIH).…”

Section: Exonuclease Enzymes Of Hhvmentioning

confidence: 99%

“…Similarly, the hydroxyquinoline carboxamide, 4 (Figure 5), was shown to have strong activity against all three nucleases that correlated well with its antiviral activity (not shown). We also tested integrase inhibitors, BXA and two 8-hydroxyquinolines (HQs), fr our library for inhibition of HSV/CMV in cell culture, as well as inhibition of puri TMID proteins [183]. The HIV integrase inhibitors showed extremely weak a HSV/CMV activity and no significant inhibition of HSV protein targets (AN and PolE [183].…”

Section: Inhibition Of Alkaline Nuclease and Pol/exo Functionmentioning

confidence: 99%

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Viral Nucleases from Herpesviruses and Coronavirus in Recombination and Proofreading: Potential Targets for Antiviral Drug Discovery

Wright

Weller

2022

Viruses

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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.

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