Drugs effective for all variants of a virus are urgently needed to fight current and future pandemics. This can be achieved by creating fusion proteins between the extracellular domains of the virus docking sites on human cells and the Fc part from a human immunoglobulin. The angiotensin-converting enzyme 2 (ACE2) is a viral receptor used by sarbeco betacorona-viruses to infect cells. Fusion proteins comprising extracellular ACE2 domains exhibit high virus neutralization efficiency, but the structure and stability of these molecules are poorly understood. Here we analyzed the structure and stability of an ACE2-IgG4-Fc. We show that the hinge between the ACE2 region and the IgG4-FC is highly flexible, and the conformational dynamics of the fusion protein is restricted by the ACE2 domain[MS1] . Interestingly, chemical compounds inhibiting the enzymatic activity of ACE2 such as DX600 and MLN4760 employ different binding mechanisms to increase the thermal stability of the ACE2 by 8.8 and 14.3 °C, respectively. In particular, MLN4760 induced allosteric effects in the ACE2 domain consistent with structural rearrangements observed in the inhibitor-bound crystal structure. Thus, our findings reveal a general concept for stabilizing the labile receptor segment of therapeutic antiviral fusion proteins[MS2] .