Infection with filoviruses such as Ebola virus can cause severe hemorrhagic fever and multiorgan failure. Broadly reactive drugs to control infection with genetically diverse filoviruses are greatly needed, as available monoclonal antibodies provide protection only against Zaire Ebola virus. Researchers have now determined the structure of Ebola virus proteins that are involved in viral replication, which could lead to the development of new drugs.
The viral RNA genome of filoviruses is associated with the polymerase complex, which consists of the large (L) protein, the cofactor viral protein 35 (VP35) and the transcription activator VP30, forming the ribonucleoprotein (RNP) complex that is responsible for viral RNA synthesis. The L–VP35 polymerase complex is highly conserved and therefore a promising drug target. Yuan et al. used cryo-electron microscopy to determine the structure of the Ebola virus L protein in complex with VP35. They showed that the L protein has a filovirus-specific insertion element that is vital for RNA synthesis, and demonstrated how VP35 interacts with the L protein. They also found that suramin — a drug that has been used to treat African sleeping sickness for about 100 years — inhibited the activity of Ebola virus polymerase, and determined the structural basis of drug inhibition. The authors note the shortcomings of suramin (including its large molecular mass and off-target effects) and state that their findings would be useful for the development of more powerful drugs against filoviruses.
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