In addition to its critical role in regulation of hypertension,
ACE2 has been demonstrated to be a functional receptor for the coronavirus that causes severe acute respiratory syndrome (SARS). The coronavirus, SARS-CoV, the primary cause of SARS, gains entry into pulmonary endothelial cells by membrane fusion on binding to this ectoenzyme. This interaction is mediated by the SARS-CoV spike protein.15–19 This conclusion is further supported by recent observations that pulmonary endothelial cells express high levels of ACE2.20 These data provide the impetus to develop ACE2 modulators with anticipation that in vivo activation of ACE2 would lead to protection and successful treatment for hypertension and other cardiovascular diseases. In contrast,
ACE2 inhibitors would be expected to block ACE2/SARS-CoV spike protein interactions and inhibit SARS-CoV infection. In addition, ACE2 inhibitors could be potentially important in the mechanisms of hypertension. Despite this urgency, only a few studies have been attempted to develop potential inhibitors and activators of ACE2.4,21,22 Our objective in this study was to determine whether a rational structure-based approach can be used to identify molecules capable of inhibiting ACE2 activity and blocking SARS-CoV based on atomic motion deduced from ACE2 crystal structures.
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