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Publications of the Week

Acquisition of the L452R Mutation in the ACE2-Binding Interface of Spike Protein Triggers Recent Massive Expansion of SARS-CoV-2 Variants

By August 31, 2021September 1st, 2021No Comments

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This week we profile a recent publication in the Journal of Clinical Microbiology from the laboratory of Dr. Evgeni Sokurenko at UW.

Can you provide a brief overview of your lab’s current research focus?

My lab is working in two major directions – molecular evolution of human pathogens and structure-functional analysis of microbial cell attachment proteins. On the evolutionary side, we are specializing in determining how the smallest genetic changes – point mutations – can increase microbial virulence or drug resistance. Here, our primary model organism is E. coli causing urinary tract and bloodstream infections. However, we apply our molecular evolutionary tools to many other human pathogens, including viruses. In regard to the cell attachment proteins, we are interested in the conformational (shape) changes of the proteins’ structure in the course of microbial attachment. This is particularly important for understanding how antibodies against those proteins can block microbial cell attachment.

What is the significance of the findings in this publication?

Our study demonstrates that one point mutation in the SARS-CoV-2 cell attachment or so-called Spike protein – replacement of leucine in the amino acid position 452 to arginine or, less commonly, glutamine (L452R/Q) – has been a trigger in the emergence of most current variants of concern or interest, including Delta. While other mutations that accompany L452R/Q are also important, none of them is as dominant as the leucine replacement. Other labs demonstrated that L452R/Q diminishes neutralizing effect of numerous monoclonal antibodies and may enhance the virus binding to the human cell receptor – ACE2. Interestingly, this mutation also might stabilize the Spike protein conformation. Thus, if any modification will be considered for the current vaccines, which are based on the original non-mutated Spike protein, it will likely benefit from focusing on L452R/Q mutants.

What are the next steps for this research?

We just received from NIH a Small Business Technology Transfer (STTR) Phase I grant with UW’s startup ID Genomics, Inc. The grant is to develop a rapid test for detection of all major variants of SARS-CoV-2 at once by focusing on the key mutations, like L452R/Q and others. So, in the near future, this will be one of the main focuses of our research on the COVID-19 virus.

If you’d like us to mention your funding sources, please list them.

Most of the current funding for my lab is from the National Institute of Allergy and Infectious Diseases of NIH, with the rest coming from the recapture funds of the Department of Microbiology of UW.

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