In a new study, researchers report the structure of remdesivir - an antiviral drug that has shown promise against the SARS-CoV-2 virus in lab studies and early clinical trials - bound to both a molecule of RNA and to the viral polymerase. The new structural information illuminates the mechanism that remdesivir uses to interrupt RNA replication and shut down viral reproduction - and may inform efforts to develop new and more potent therapies that employ a similar mechanism. As the enzyme that catalyzes the synthesis of viral RNA for SARS-CoV-2, thus playing a central role in its replication, the polymerase is a primary target for fighting the virus. Prior work had reported the structure of the polymerase - an RNA-dependent RNA polymerase - using cryo-electron microscopy (cryo-EM). Wanchao Yin and colleagues took this further by again imaging the polymerase, which consists of four subunits - nsp12, nsp7, and two units of nsp8 - using cryo-EM at 2.8 angstrom resolution, obtaining results consistent with the previously determined structure. They then imaged a complex of the polymerase bound to both an RNA template and to a molecule of remdesivir, using cryo-EM at 2.5 angstrom resolution. In its active form, remdesivir mimics the structure of adenosine, a nucleoside that is incorporated into RNA during replication. When the drug, instead of a nucleoside, is added to a new RNA molecule it blocks further synthesis of viral RNA. The detailed cryo-EM structural information enabled Yin et al. to pinpoint the precise residues of the polymerase that interact with both the RNA template and remdesivir. These insights, in turn, will inform efforts to design more effective therapies that also mimic nucleosides to disrupt viral replication, and may lead to better understanding of existing nucleoside mimic drugs such as EIDD-2801, ribavirin, galidesivir, and favipiravir, the authors suggest.
