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The spread of coronavirus diseases has resulted in a clarion call to develop potent drugs and vaccines even as different strains appear beyond human prediction. An initial step that is integral to the viral entry into host cells results from an active-targeted interaction of the viral spike (S) proteins and the cell surface receptor, called angiotensin-converting enzyme 2 (ACE2). Thus, engineered ACE2 has been an interesting decoy inhibitor against emerging coronavirus infestation. This article discusses promising innovative ACE2 engineering pathways for current and emerging coronavirus therapeutic development. First, we provide a brief discussion of some ACE2-associated human coronaviruses and their cell invasion mechanism. Then, we describe and contrast the individual spike proteins and ACE2 receptor interactions, highlighting crucial hotspots across the ACE2-associated coronaviruses. Lastly, we address …