A First Step in a Paramyxo Drug: Defining the Polymerase Complex Structure

Paramyxoviridae is an important viral family that includes diseases such as measles, mumps, respiratory syncytial virus (RSV) and human parainfluenza. As it stands, there are no specific antiviral treatments for any member of the paramyxo family. The pervasiveness and severe complications associated with paramyxoviruses make it essential for researchers to develop therapies against infection, but without knowledge of viral protein structures, drug design is really a “guess-and-check” type process. Recently, a team of researchers used cryogenic electron microscopy (cryo-EM) to uncover the structure of the parainfluenza polymerase (L-protein) and its cofactor (P-protein) together called the L-P complex. Cryo-EM essentially launches a stream of electrons at a frozen protein sample to put together a flurry of 2-D images into a reconstructed 3-D depiction with higher resolution than traditional electron microscopy. In the massive 5-protein, 2000 amino acid complex, the researchers found new, unidentified proteins and a unique methyltransferase conformation. They believe it is responsible for promoting the switch between transcription and replication. The in-depth knowledge about the key proteins’ structure will make it a viable potential drug candidate for antivirals. This research will help create new drugs not only for parainfluenza and other paramyxoviruses, but also for other viruses in the mononegavirales order with similar polymerase complexes and “switching” mechanisms.

~Avi Kaye

Article: Abdella et al. Structure of a paramyxovirus polymerase complex reveals a unique methyltransferase-CTD conformation. PNAS, 2020. https://doi.org/10.1073/pnas.1919837117