[HTML][HTML] Novel broad spectrum inhibitors targeting the flavivirus methyltransferase
M Brecher, H Chen, B Liu, NK Banavali, SA Jones… - PLoS …, 2015 - journals.plos.org
PLoS One, 2015•journals.plos.org
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 …
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 …
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.
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