Nucleosides for the treatment of respiratory RNA virus infections

Jordan, Paul C; Stevens, Sarah K; Deval, Jerome

Proteins and enzymes rarely exist in a monomeric state in nature but are energetically driven to higher order, oligomeric states through polar and hydrophobic interactions and disulfide bond formation. The development of increasingly sophisticated structural biology techniques, including high-resolution X-ray crystal structures and cryo-EM, has provided a snapshot into how polymerases may adopt such oligomeric states. The understanding and characterization of the oligomeric states place these multifunctional enzymes in a greater biological context. An example of such oligomeric states and how this impacts the catalytic function is the polymerase from PV. PV RdRp is described as having macromolecular contacts at two polymerase interfaces (Interface I and Interface II). 94 Interface I is defined by the interaction of the thumb domain from one polymerase with the palm of another polymerase. Interface II describes interactions of the N-terminus of one polymerase with the thumb of a neighboring polymerase within the crystal lattice. Additionally, PV can form tube-like structures suggesting it is a highly dynamic structure able to undergo and adopt multiple conformational arrangements. 95 The oligomeric state of PV polymerase is required for membrane-associated RNA replication in infected cells, as demonstrated by mutating residues involved in protein-protein interactions. 96, 97 The polymerase of CoV