How new insights into COVID's spike protein could guide treatment design

31 March 2021

Arlene Weintraub / FiercePharma

SARS-CoV-2, the virus behind the COVID-19 pandemic, is structurally similar to SARS-CoV-1, the virus that caused a much smaller outbreak two decades ago. So why has today’s iteration of the virus been so much more infectious?

Researchers at Lehigh University say they have found one clue to solving that mystery, and it lies in the method by which the virus interacts with cells.

The spike protein on both coronaviruses interacts with angiotensin-converting enzyme 2 (ACE2) receptors to gain entry to cells, but the bond between them is stronger with SARS-CoV-2 than it is with the original virus. The Lehigh team discovered that the strong bond is related to a previously unknown interaction between sugars, or glycans, on the surface of ACE2 and SARS-CoV-2’s spike protein, they reported in Biophysical Journal.

The discovery could explain why SARS-CoV-2 has a higher infection rate than SARS-CoV-1, and it could offer insights to aid the development of new therapies for COVID-19, the Lehigh team said.

The researchers used advanced bioengineering techniques to characterize the interactions among proteins as SARS-CoV-2 invaded cells. They deployed a technology for single-molecule detection they developed to measure the force of the interaction between the spike protein and ACE2.

To prove ACE2 glycans were responsible for the strong glue holding SARS-CoV-2 to cells, the team removed the sugars and measured the force of the interaction again. The strength of the bond “fell back to levels similar to SARS-CoV-1," said co-author X. Frank Zhang, Ph.D., an associate professor of engineering at Lehigh, in a statement.

The role of glycans in the spread of COVID-19 has been of interest to other academic teams, too. Last fall, a team at the University of California, San Diego explained how N-glycans at two sites on SARs-CoV-2 promote viral infection. They suggested the discovery could improve vaccine design.

More recently, Yale University scientists described how the spike protein changes shape to avoid being attacked by antibodies, and they offered insights into how to best target the protein with drugs to prevent and treat the virus.

The Lehigh team noted in the new study that further investigation would be needed to determine the exact role of SARS-CoV-2 glycans in the transmission of COVID-19. "Our hope is that researchers may be able to use this information to develop new strategies to identify, prevent, treat and vaccinate against COVID-19," Zhang said.

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