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Novel Broad Spectrum Inhibitors Targeting the Flavivirus Methyltransferase.

Brecher M, Chen H, Liu B, Banavali NK, Jones SA, Zhang J, Li Z, Kramer LD, Li H - PLoS ONE (2015)

Bottom Line: The flavivirus methyltransferase (MTase) is an essential enzyme that sequentially methylates the N7 and 2'-O positions of the viral RNA cap, using S-adenosyl-L-methionine (SAM) as a methyl donor.In vitro methylation experiments demonstrated significant MTase inhibition by 13 of these compounds, with the most potent compound displaying sub-micromolar inhibitory activity.The most active compounds showed broad spectrum activity against the MTase proteins of multiple flaviviruses.

View Article: PubMed Central - PubMed

Affiliation: Wadsworth Center, New York State Department of Health, 120 New Scotland Ave, Albany, NY, 12208 United States of America.

ABSTRACT
The flavivirus methyltransferase (MTase) is an essential enzyme that sequentially methylates the N7 and 2'-O positions of the viral RNA cap, using S-adenosyl-L-methionine (SAM) as a methyl donor. We report here that small molecule compounds, which putatively bind to the SAM-binding site of flavivirus MTase and inhibit its function, were identified by using virtual screening. In vitro methylation experiments demonstrated significant MTase inhibition by 13 of these compounds, with the most potent compound displaying sub-micromolar inhibitory activity. The most active compounds showed broad spectrum activity against the MTase proteins of multiple flaviviruses. Two of these compounds also exhibited low cytotoxicity and effectively inhibited viral replication in cell-based assays, providing further structural insight into flavivirus MTase inhibition.

No MeSH data available.


Schematic formulas of selected compounds showing in vitro anti-MTase activities.
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pone.0130062.g003: Schematic formulas of selected compounds showing in vitro anti-MTase activities.

Mentions: Using the WNV MTase as a model, we measured both the N7 and 2’-O MTase activities of the WNV MTase in the presence of the 42 top-ranked compounds at a concentration of 150 μM with SIN as a positive control. As shown in fig 2, the positive control inhibitor SIN efficiently inhibited (~80%) the N7 activity of the WNV MTase. At 150 μM concentration, 13 out of the 42 compounds inhibited the WNV MTase N7 MTase activity by more than 60% (figs 2 and 3). Compared to the inhibition of the N7 MTase activity, the 2’-O inhibition by these compounds varied (fig 2). Similar variations of inhibitions of the N7 and 2’-O MTase activities by identical compounds have been observed previously [26, 30]. For example, SAH was reported to require 6-fold lower IC50 concentration for inhibitions of 2’-O than of N7 [39]. As only the N7 MTase activity is essential for the virus replication [10, 33], these 13 compounds were chosen for further analyses, although some of them showed no inhibition towards the 2’-O MTase activity.


Novel Broad Spectrum Inhibitors Targeting the Flavivirus Methyltransferase.

Brecher M, Chen H, Liu B, Banavali NK, Jones SA, Zhang J, Li Z, Kramer LD, Li H - PLoS ONE (2015)

Schematic formulas of selected compounds showing in vitro anti-MTase activities.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476580&req=5

pone.0130062.g003: Schematic formulas of selected compounds showing in vitro anti-MTase activities.
Mentions: Using the WNV MTase as a model, we measured both the N7 and 2’-O MTase activities of the WNV MTase in the presence of the 42 top-ranked compounds at a concentration of 150 μM with SIN as a positive control. As shown in fig 2, the positive control inhibitor SIN efficiently inhibited (~80%) the N7 activity of the WNV MTase. At 150 μM concentration, 13 out of the 42 compounds inhibited the WNV MTase N7 MTase activity by more than 60% (figs 2 and 3). Compared to the inhibition of the N7 MTase activity, the 2’-O inhibition by these compounds varied (fig 2). Similar variations of inhibitions of the N7 and 2’-O MTase activities by identical compounds have been observed previously [26, 30]. For example, SAH was reported to require 6-fold lower IC50 concentration for inhibitions of 2’-O than of N7 [39]. As only the N7 MTase activity is essential for the virus replication [10, 33], these 13 compounds were chosen for further analyses, although some of them showed no inhibition towards the 2’-O MTase activity.

Bottom Line: The flavivirus methyltransferase (MTase) is an essential enzyme that sequentially methylates the N7 and 2'-O positions of the viral RNA cap, using S-adenosyl-L-methionine (SAM) as a methyl donor.In vitro methylation experiments demonstrated significant MTase inhibition by 13 of these compounds, with the most potent compound displaying sub-micromolar inhibitory activity.The most active compounds showed broad spectrum activity against the MTase proteins of multiple flaviviruses.

View Article: PubMed Central - PubMed

Affiliation: Wadsworth Center, New York State Department of Health, 120 New Scotland Ave, Albany, NY, 12208 United States of America.

ABSTRACT
The flavivirus methyltransferase (MTase) is an essential enzyme that sequentially methylates the N7 and 2'-O positions of the viral RNA cap, using S-adenosyl-L-methionine (SAM) as a methyl donor. We report here that small molecule compounds, which putatively bind to the SAM-binding site of flavivirus MTase and inhibit its function, were identified by using virtual screening. In vitro methylation experiments demonstrated significant MTase inhibition by 13 of these compounds, with the most potent compound displaying sub-micromolar inhibitory activity. The most active compounds showed broad spectrum activity against the MTase proteins of multiple flaviviruses. Two of these compounds also exhibited low cytotoxicity and effectively inhibited viral replication in cell-based assays, providing further structural insight into flavivirus MTase inhibition.

No MeSH data available.