Agonism of receptors activated by ACE2-derived peptides
Ang (1-7) is considered the major ACE2-derived peptide but ACE2 can also generate other peptides, including Ang (1-9) and the heptapeptide alamandine. Ang (1-7) primarily acts via the Mas-1 receptor (Figure 2 ) while response to Ang (1-9) may also involve AT2R; alamandine has effects similar to Ang (1-7) via interactions with the Mas-related GPCR, member D (MrgD) (Alexander at al., 2019).  The actions of the ACE2-Ang (1-7)-Mas-1 receptor, ACE2-Ang (1-9)-AGTR2 and ACE2-alamandine-MrgD pathways generally oppose those of the Ang II-AGRT1 pathway, though this remains controversial for AGTR2, as discussed earlier in this text. Activation of the former pathways, in particular via GPCRs that mediate their effects, is thus predicted to blunt COVID-19 pathobiology. Signaling by ANG (1-7) via Mas-1 can increase activity of MAP kinase, phosphoinositide 3-kinase/Akt and NADPH oxidase and subsequently activate effectors that include forkhead box protein 01 (FOXO1), cyclcooxygenase 2 (COX2) and generation of prostanoids and nitric oxide (NO) (Santos et al., 2019; Povlsen et al., 2020). Less is currently known regarding alamandine signaling and action. Additional peptides may be generated as part of non-canonical (“non-classic”) Ang II signaling (Santos et al, 2019), Efforts are underway to discover and develop drugs that mimic the physiological peptides in their actions on Mas-1 and Mrgd receptors. Initial clinical studies have tested an oral formulation of hydroxypropyl-β-cyclodextrin-ANG-(1−7) on muscle injury (Becker et al., 2018). As recently reviewed (Wang et al., 2019), targeting of non-canonical Ang signaling pathways has also been initiated in studies of ARDS. Such approaches should be highly suitable for testing in patients with COVID-19.