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Published on: February 6, 2017
Macrodomain Binding Compound MRS 2578 Inhibits Alphavirus Replication
Sari Mattila1, Pirjo Merilahti1, Sarah Wazir2
1Department of Microbiology, Faculty of Agriculture and Forestry, University of Helsinkigrid.7737.4, Helsinki, Finland.
Abstract:
Alphaviruses are positive-strand RNA viruses causing febrile disease. Macrodomain-containing proteins, involved in ADP-ribose-mediated signaling, are encoded by both host cells and several virus groups, including alphaviruses. In this study, compound MRS 2578 that targets the human ADP-ribose glycohydrolase MacroD1 inhibited Semliki Forest virus production as well as viral RNA replication and replicase protein expression. The inhibitor was similarly active in alphavirus trans-replication systems, indicating that it targets the viral RNA replication stage.
Insights
A novel compound targeting MacroD1, an ADP-ribose glycohydrolase, effectively inhibited Semliki Forest virus production. This suggests MacroD1 is a potential target for antiviral therapies against alphaviruses.
Area of Science:
- Virology
- Molecular Biology
- Biochemistry
Background:
- Alphaviruses are positive-strand RNA viruses responsible for febrile illnesses.
- Macrodomain-containing proteins regulate ADP-ribose signaling and are found in hosts and viruses.
- MacroD1 is a human ADP-ribose glycohydrolase.
Purpose of the Study:
- To investigate the role of MacroD1 in alphavirus replication.
- To evaluate the efficacy of a MacroD1 inhibitor, MRS 2578, against alphavirus infection.
Main Methods:
- Treatment of Semliki Forest virus-infected cells with compound MRS 2578.
- Assessment of viral production, RNA replication, and replicase protein expression.
- Evaluation of MRS 2578 activity in alphavirus *trans*-replication systems.
Main Results:
- Compound MRS 2578 significantly inhibited Semliki Forest virus production.
- The inhibitor reduced viral RNA replication and replicase protein expression.
- MRS 2578 demonstrated efficacy in *trans*-replication assays, pinpointing the viral RNA replication stage.
Conclusions:
- The human ADP-ribose glycohydrolase MacroD1 plays a role in alphavirus replication.
- Compound MRS 2578, by targeting MacroD1, effectively inhibits alphavirus RNA replication.
- MacroD1 is a potential therapeutic target for controlling alphavirus infections.
