Effect of natural and engineered variations on structure and biophysics of SARS-CoV-2 spike

Effect of natural and engineered variations on structure and biophysics of SARS-CoV-2 spike
COVID-19, caused by SARS-CoV-2, has devasted global health and economics. Vaccines are being
deployed worldwide to gain control of the pandemic, although emergence of fast-spreading “variants of
concern” (VOCs) have caused concern. Mutations in the spike (S) protein are under scrutiny due to its
essential role in the virus life cycle, and being the dominant target of neutralizing antibodies. Widespread
vaccine hesitancy and the current spread of the Delta variant provide fertile ground for emergence of vaccine-
resistant variants. We and others have shown that variants use a plethora of strategies to modify antibody and
receptor interactive surfaces, and spike conformation, resulting in antibody evasion and greater infectivity.
Over the last two years, utilizing urgent supplement funding from the NIH, we studied the structures of SARS-
CoV-2 S proteins and have established workflows spanning structure, biochemistry, biophysics and
computation. Here we propose to continue the essential work of detangling the effects of variant S protein
mutations, and to enhance our understanding of spike structure to further efforts to predict where the virus is
heading and to inform novel vaccine designs. The scientific premise of this grant is that understanding spike
structure and allostery will provide insights into its function, inform vaccine development, and provide
mechanistic information essential for relating spike structure to beta-CoV replication, evolution, and immune
evasion. The innovations in this grant derive from technologies we have developed for structural analyses of
the S protein: an integrative structural biology pipeline combines cryo-electron microscopy (cryo-EM), Negative
Stain Electron Microscopy (NSEM) and X-ray crystallography, with computational methods, and biochemical
and biophysical analyses to study structural and functional properties of the spike, including furin cleavage,
receptor binding, and antigenicity.

Grant Number: 5R01AI165947-04
NIH Institute/Center: NIH
Principal Investigator: Priyamvada Acharya