BioAFM Journal Club

Molecular Interaction and Inhibition of SARS-CoV-2 Binding to the ACE2 Receptor

by Jinsung Yang, Simon J. L. Petitjean, Melanie Koehler, Qingrong Zhang, Andra C. Dumitru, Wenzhang Chen, Sylvie Derclaye, Stéphane P. Vincent, Patrice Soumillion & David Alsteens

Nature Communications 11, Article number: 4541 (2020)

A highly relevant article on how AFM-based single-molecule dynamic force spectroscopy, coupled with confocal microscopy, can contribute towards understanding the kinetics and thermodynamics of a SARS-CoV-2 infection.

We are, currently, all aware of the drastic effects viruses can have on our lives. To date, multiple vaccines have been approved for use against the SARS-CoV-2 virus, with more vaccines expected in the near future. For an infection to occur, the virus must recognize a structure on the host cell that it can bind to. For SARS-CoV-2 (or its S-glycoprotein), it is the angiotensin-converting enzyme 2 (ACE2) receptor on the surface of host cells. But what do we know about this interaction and can we inhibit it?

To address these questions, a group of researchers from Université catholique de Louvain lead by Prof. Alsteens, performed AFM-based, single-molecule, dynamic force spectroscopy to extract the kinetics and thermodynamics of the interaction in vitro. The tests were performed on surfaces grafted with covalently immobilized ACE2 receptors and living A549 alveolar epithelial cells transfected with ACE2-eGFP. The AFM probes were functionalized with either a S1 subunit of virus glycoprotein or with a receptor binding domain (RBD) of it only. Short ACE2-derived peptides (7 to 36 aa) were tested as potential interaction inhibitors and showed a significant reduction in binding. The Bruker BioScope Resolve AFM coupled with a confocal microscope operated in Force-Volume (grafted surfaces) and in PeakForce Quantitative Nanomechanical mode (transfected cells) was used in this study.

The findings of the authors show that SARS-CoV-2 binding to ACE2 is dominated by the RBD/ACE2 interface, and that short ACE2-derived peptides (especially those mimicking N-terminal helix of ACE2) show inhibition properties, and could, therefore, potentially be used as therapeutic candidates against SARS-CoV-2 infections.