Structural biology in the time of COVID-19: perspectives on methods and milestones

Abstract

The global COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has wreaked unprecedented havoc on global society, in terms of a huge loss of life and burden of morbidity, economic upheaval and social disruption. Yet the sheer magnitude and uniqueness of this event has also spawned a massive mobilization of effort in the scientific community to investigate the virus, to develop therapeutics and vaccines, and to understand the public health impacts. Structural biology has been at the center of these efforts, and so it is advantageous to take an opportunity to reflect on the status of structural science vis-à-vis its role in the fight against COVID-19, to register the unprecedented response and to contemplate the role of structural biology in addressing future outbreak threats. As the one-year anniversary of the World Health Organization declaration that COVID-19 is a pandemic has just passed, over 1000 structures of SARS-CoV-2 biomolecules have been deposited in the Worldwide Protein Data Bank (PDB). It is rare to obtain a snapshot of such intense effort in the structural biology arena and is of special interest as the 50th anniversary of the PDB is celebrated in 2021. It is additionally timely as it overlaps with a period that has been termed the `resolution revolution' in cryoelectron microscopy (CryoEM). CryoEM has recently become capable of producing biomolecular structures at similar resolutions to those traditionally associated with macromolecular X-ray crystallography. Examining SARS-CoV-2 protein structures that have been deposited in the PDB since the virus was first identified allows a unique window into the power of structural biology and a snapshot of the advantages of the different techniques available, as well as insight into the complementarity of the structural methods.

Structure-based approaches against COVID-19

“…They have been vital since the beginning of the pandemic in helping researchers understand the whole virus and virus-host interactions, 4,5 particularly based on super-high-resolution structures of all viral proteins. [6][7][8] www.ejcma.org Huang et al…”

Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses

“… 13 These libraries provide opportunities to identify potential therapeutic agents that can readily be synthesized and tested for activity but require development of effective strategies for navigation in this enormous chemical space. The determination of high-resolution crystal structures of SARS-CoV-2 proteins 14 has enabled virtual screening campaigns to identify hits that can be developed into antiviral drugs. Structure-based docking algorithms can sample and score binding poses in seconds, making it possible to evaluate large libraries, and this approach is not restricted to compounds that are physically available.…”

Structure determination needs to go viral

“…In the case of SARS-CoV-2, there was an unprecedented output of resolved viral protein structures in a very short period of time (Lynch et al 2021 ). A similar effort has only been seen for HIV, albeit on a much smaller scale in a much longer period of time (Engelman and Cherepanov 2012 ).…”