Title
Extrinsic Stabilization of Antiviral ACE2-Fc Fusion Proteins Targeting SARS-CoV-2
Author
Svilenov, Hristo L., Florent Delhommel, Till Siebenmorgen, Florian Rührnößl, Grzegorz M. Popowicz, Alwin Reiter, Michael Sattler, Carsten Brockmeyer, and Johannes Buchner
Year
2023
Journal
Communications Biology
Abstract
The angiotensin-converting enzyme 2 (ACE2) is a viral receptor used by sarbecoviruses to infect cells. Fusion proteins comprising extracellular ACE2 domains and the Fc part of immunoglobulins exhibit high virus neutralization efficiency, but the structure and stability of these molecules are poorly understood. We show that although the hinge between the ACE2 and the IgG4-Fc is highly flexible, the conformational dynamics of the two ACE2 domains is restricted by their association. Interestingly, the conformational stability of the ACE2 moiety is much lower than that of the Fc part. We found that chemical compounds binding to ACE2, such as DX600 and MLN4760, can be used to strongly increase the thermal stability of the ACE2 by different mechanisms. Together, our findings reveal a general concept for stabilizing the labile receptor segments of therapeutic antiviral fusion proteins by chemical compounds.
Full Article
Instrument
J-1500
Keywords
Therapeutic antiviral fusion proteins