Application of Cryoelectron Microscopy in Antiviral Research

In the last decade, single-particle reconstruction from cryoelectron micrographs has been established as a powerful technique for generating high-resolution structures of biological macromolecules. In comparison to conventional methods such as X-ray crystallography and nuclear magnetic resonance, cryogenic electron microscopy (cryoEM) does not require large quantities of starting material or crystallization of biomolecules. The preservation of biomolecules at near-native states and the ability to characterize large complexes, transition states, and heterogeneous and dynamic systems make this method valuable for effective drug development against viral diseases. While there are challenges associated with the utilization of cryoEM as a high-throughput method for drug discovery, the issues are not insurmountable in the near future. The establishment of antiviral discovery pipelines is a crucial scientific activity in the current scenario, given the human health crisis and economic hardships precipitated by the recent pandemic and strong prospects for the emergence or re-emergence of epidemic or pandemic viral strains. The prioritization of high-resolution structure determination of viral proteins and protein complexes is essential as it will aid in drug discovery. In this chapter, we discuss the advantages of cryoEM over other structural biology methods, followed by prevailing drug discovery techniques, the current and potential contribution of cryoEM to virus-specific structure determination and identification and validation of drug candidates, and the future prospects of the technique. Although efforts have been made to include as many recent studies in this area as possible, the vastness of the topic has precluded the inclusion of all such studies.