Inhibitors of the Small Membrane (M) Protein Viroporin Prevent Zika Virus Infection

Brown, Emma; Lefteri, Daniella; Singh, Rahul; Thompson, Rebecca; Maskell, Daniel P.; Beaumont, Hannah; Mj, Bentham; Swinscoe, Gemma; Merits, Andres; Donald, Claire L.; Kohl, Alain; Macdonald, Andrew; Ranson, Neil A.; Foster, Richard; McKimmie, Clive S.; Ac, Kalli; Griffin, Stephen

doi:10.1101/2021.03.11.435022

Cited by 5 publications

(12 citation statements)

References 82 publications

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“…The blockage of this putative viroporin could be the mechanism of action of the herein tested adamantanes against ZIKV (Figure 4, Table 1). We found support to this hypothesis in the preliminary work from Brown and collaborators [58]. This research group demonstrated a reduction in ZIKV envelope protein (E) expression in Vero cells upon treatment with the viroporin inhibitor, rimantadine, in a dose dependent manner.…”

Section: Discussionsupporting

confidence: 60%

In Vitro Inhibition of Zika Virus Replication with Amantadine and Rimantadine Hydrochlorides

Arias-Arias¹,

Vega-Aguilar²,

Picado-Soto³

et al. 2021

Preprint

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Zika virus (ZIKV) is a mosquito-born flavivirus which human infection became relevant dur-ing recent outbreaks in Latin America, due to its unrecognized association with fetal neurologi-cal disorders. Currently there are no approved effective antivirals or vaccines for treatment or prevention of ZIKV infections. Amantadine and rimantadine are approved antivirals used against susceptible influenza A virus infections, that have been shown to have antiviral activity against other viruses, such as dengue virus (DENV). Here, we report the in vitro effectiveness of both amantadine and rimantadine hydrochlorides against ZIKV replication, resulting in a dose-dependent reduction in viral titers of a ZIKV clinical isolate and two different ZIKV refer-ence strains. Additionally, we demonstrate similar in vitro antiviral activity of these drugs against DENV-1 and yellow fever virus (YFV), although at higher drug concentrations for the later. ZIKV replication was inhibited at drug concentrations well below cytotoxic levels of both compounds, as denoted by the high selectivity indexes obtained with the tested strains. Further work is absolutely needed to determine a potential clinical use of these antivirals against ZIKV infections, but our results suggest the existence of a highly conserved mechanism across fla-vivirus, susceptible to be blocked by modified more specific adamantane compounds.

show abstract

Section: Discussionsupporting

confidence: 60%

In Vitro Inhibition of Zika Virus Replication with Amantadine and Rimantadine Hydrochlorides

Arias-Arias¹,

Vega-Aguilar²,

Picado-Soto³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…The blockage of this putative viroporin could be the mechanism of action of the herein tested adamantanes against ZIKV (Figure 4, Table 1). We found support to this hypothesis in the preliminary work from Brown and collaborators [58]. This research group demonstrated a reduction in the ZIKV envelope protein (E) expression in Vero cells upon treatment with the viroporin inhibitor, rimantadine, in a dose dependent manner.…”

Section: Discussionsupporting

confidence: 59%

“…Indeed, they combined molecular dynamic simulations with biochemical approaches to provide evidence that ZIKV M protein functions as a rimantadine-sensitive viroporin within virion membranes, with a potential role during the entry and uncoating of infectious viral particles. They also used in vivo ZIKV preclinical models to demonstrate that rimantadine reduces viraemia, supporting that M protein channel activity is a relevant physiological target to block ZIKV infection [58].…”

Section: Discussionmentioning

confidence: 92%

In Vitro Inhibition of Zika Virus Replication with Amantadine and Rimantadine Hydrochlorides

Arias-Arias

Vega-Aguilar

Picado-Soto

et al. 2021

Microbiology Research

View full text Add to dashboard Cite

Zika virus (ZIKV) is a mosquito-borne flavivirus in which human infection became relevant during recent outbreaks in Latin America due to its unrecognized association with fetal neurological disorders. Currently, there are no approved effective antivirals or vaccines for the treatment or prevention of ZIKV infections. Amantadine and rimantadine are approved antivirals used against susceptible influenza A virus infections that have been shown to have antiviral activity against other viruses, such as dengue virus (DENV). Here, we report the in vitro effectiveness of both amantadine and rimantadine hydrochlorides against ZIKV replication, resulting in a dose-dependent reduction in viral titers of a ZIKV clinical isolate and two different ZIKV reference strains. Additionally, we demonstrate similar in vitro antiviral activity of these drugs against DENV-1 and yellow fever virus (YFV), although at higher drug concentrations for the latter. ZIKV replication was inhibited at drug concentrations well below cytotoxic levels of both compounds, as denoted by the high selectivity indexes obtained with the tested strains. Further work is absolutely needed to determine the potential clinical use of these antivirals against ZIKV infections, but our results suggest the existence of a highly conserved mechanism across flavivirus, susceptible to be blocked by modified more specific adamantane compounds.

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“…Our data highlighted a major role for M residue 36 in proper folding of DENV-2 E protein and proapoptotic activity of ApoptoM. There is mounting evidence that small integral M protein is involved in flavivirus morphogenesis and infection processes [19,20,31,33,38]. It is therefore of priority to generate infectious molecular clones derived from RUN-18 and DES-14 to better understand the role of M residue 36 on the pathogenicity of contemporary SWIO DENV-2 strains.…”

Section: Discussionmentioning

confidence: 84%

The hydrophobic nature of dengue 2 M residue 36 influences E protein and ApoptoM peptide

Decotter

Després

Gadéa³

2023

Preprint

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The recent epidemics of dengue in South West Indian Ocean coincided with the emergence of Cosmopolitan dengue virus type 2, including viral strains DES-14 in Tanzania and then RUN-18 in La Reunion. The initial step of dengue virus assembly is the formation of heterodimers between prM and E proteins where prM acts as a chaperone for E. During dengue virus maturation, prM is cleaved into membrane protein M which embeds a pro-apoptotic peptide consisting of residues 31/41 and referred as ApoptoM. An infrequent valine at position M-36 was found in DES-14 whereas RUN-18 bears a common isoleucine. Here, we investigated whether Ile-to-Val substitution at position M-36 may have an impact on RUN-18 E expression and cell-death promoting capability of RUN-18 ApoptoM. Using recombinant RUN-18 envelope proteins expressed in human epithelial A549 cells, we showed that Ile-to-Val but not Ile-to-Ala substitution affects the behavior E protein reducing the cytotoxicity of prM and E proteins. The substitution of isoleucine by valine at position M-36 leads to increase the apoptosis-inducing activity of ApoptoM. Our data highlight that hydrophobic nature of amino-acid residue in position 36 of dengue virus M protein influences E protein expression and death-promoting activity of ApoptoM opens up important perspectives in the development of effective live-attenuated DENV vaccines.

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Inhibitors of the Small Membrane (M) Protein Viroporin Prevent Zika Virus Infection

Cited by 5 publications

References 82 publications

In Vitro Inhibition of Zika Virus Replication with Amantadine and Rimantadine Hydrochlorides

In Vitro Inhibition of Zika Virus Replication with Amantadine and Rimantadine Hydrochlorides

In Vitro Inhibition of Zika Virus Replication with Amantadine and Rimantadine Hydrochlorides

The hydrophobic nature of dengue 2 M residue 36 influences E protein and ApoptoM peptide

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