A new paradigm in viral resistance

Ruiz, Autumn; Russell, Stephen J.

doi:10.1038/cr.2012.139

Cited by 6 publications

(4 citation statements)

References 14 publications

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“…Thus, a potentially better approach for the development of novel antiviral therapeutics would be to target host factors required for viral replication, although cytotoxicity of such antiviral agents is of considerable importance. Targeting host factors could have a significant impact on multiple virus genotypes (strain/serotype) and could provide broad spectrum inhibition against different families of viruses which might use the same cellular pathway(s) for replication (Pawlotsky, 2012; Ruiz and Russell, 2012; Conteduca et al., 2014; Shahidi et al., 2014; Khandelwal et al., 2017). This novel approach has led to the development of some promising compounds for the treatment of HCV and HIV (Gilliam et al., 2011; von Hahn et al., 2011).…”

Section: Discussionmentioning

confidence: 99%

Inhibitor of Sarco/Endoplasmic Reticulum Calcium-ATPase Impairs Multiple Steps of Paramyxovirus Replication

et al. 2019

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Sarco/endoplasmic reticulum calcium-ATPase (SERCA) is a membrane-bound cytosolic enzyme which is known to regulate the uptake of calcium into the sarco/endoplasmic reticulum. Herein, we demonstrate for the first time that SERCA can also regulate virus replication. Treatment of Vero cells with SERCA-specific inhibitor (Thapsigargin) at a concentration that is nontoxic to the cells significantly reduced Peste des petits ruminants virus (PPRV) and Newcastle disease virus (NDV) replication. Conversely, overexpression of SERCA rescued the inhibitory effect of Thapsigargin on virus replication. PPRV and NDV infection induced SERCA expression in Vero cells, which could be blocked by Thapsigargin. Besides inducing enhanced formation of cytoplasmic foci, Thapsigargin was shown to block viral entry into the target cells as well as synthesis of viral proteins. Furthermore, NDV was shown to acquire significant resistance to Thapsigargin upon long-term passage (P) in Vero cells. As compared to the P0 and P70-Control, the fusion (F) protein of P70-Thapsigargin virus exhibited a unique mutation at amino acid residue 104 (E104K), whereas no Thapsigargin-associated mutations were observed in HN gene. To the best of our knowledge, this is the first report describing the virus-supportive role of SERCA and a rare report suggesting that viruses may acquire resistance even in the presence of an inhibitor that targets a cellular factor.

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Section: Discussionmentioning

confidence: 99%

Inhibitor of Sarco/Endoplasmic Reticulum Calcium-ATPase Impairs Multiple Steps of Paramyxovirus Replication

et al. 2019

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“…RNA viruses, in particular, have high mutation rates owing to their error-prone polymerases and rapidly generating drug-resistant variants (8)(9)(10). On this basis, blocking host cell factors required by different viruses for their replication might be a low cost and short time but effective route to develop broad spectrum antivirals able to limit the occurrence of drug resistance (11,12).…”

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confidence: 99%

Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents

Brai

Fazi

Tintori

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

102

110

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Targeting a host factor essential for the replication of different viruses but not for the cells offers a higher genetic barrier to the development of resistance, may simplify therapy regimens for coinfections, and facilitates management of emerging viral diseases. DEADbox polypeptide 3 (DDX3) is a human host factor required for the replication of several DNA and RNA viruses, including some of the most challenging human pathogens currently circulating, such as HIV-1, Hepatitis C virus, Dengue virus, and West Nile virus. Herein, we showed for the first time, to our knowledge, that the inhibition of DDX3 by a small molecule could be successfully exploited for the development of a broad spectrum antiviral agent. In addition to the multiple antiviral activities, hit compound 16d retained full activity against drug-resistant HIV-1 strains in the absence of cellular toxicity. Pharmacokinetics and toxicity studies in rats confirmed a good safety profile and bioavailability of 16d. Thus, DDX3 is here validated as a valuable therapeutic target.broad spectrum antivirals | DDX3 | host factors | resistance | coinfections

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“…Thus, a potentially better approach for development of novel antiviral therapeutics would be to target host factors required for viral replication. Targeting host factors could have a significant impact on multiple virus genotypes (strain/serotype) and provide broad spectrum inhibition against different families of viruses which might use the same cellular pathway(s) for replication (24, 30-33). This novel approach has led to the development of some promising compounds for treatment of HCV and HIV (34, 35).…”

Section: Discussionmentioning

confidence: 99%

Inhibitor of sarco/endoplasmic reticulum calcium-ATPase impairs paramyxovirus replication

Kumar

Barua

Tripathi

et al. 2018

Preprint

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21Sarco/endoplasmic reticulum calcium-ATPase (SERCA) is a membrane bound 22 cytosolic enzyme that is known to regulate the uptake of calcium into the 23 sarco/endoplasmic reticulum. Herein, we demonstrate for the first time that SERCA can 24 also regulate paramyxovirus [Peste des petits ruminants virus (PPRV) and Newcastle 25 disease virus (NDV)] replication. Treatment of Vero cells with SERCA specific 26 inhibitor (Thapsigargin) at a concentration that is nontoxic to the cells significantly 27 reduced virus replication. Conversely, overexpression of SERCA rescued the inhibitory 28 effect of Thapsigargin on virus replication. PPRV/NDV infection induced SERCA 29 expression in Vero cells which could be blocked by Thapsigargin. With the help of 30 time-of-addition and virus step-specific assays, it was observed that Thapsigargin 31 specifically inhibits viral entry and subcellular localization of the viral proteins. 32

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A new paradigm in viral resistance

Cited by 6 publications

References 14 publications

Inhibitor of Sarco/Endoplasmic Reticulum Calcium-ATPase Impairs Multiple Steps of Paramyxovirus Replication

Inhibitor of Sarco/Endoplasmic Reticulum Calcium-ATPase Impairs Multiple Steps of Paramyxovirus Replication

Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents

Inhibitor of sarco/endoplasmic reticulum calcium-ATPase impairs paramyxovirus replication

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