Novel Variants of Angiotensin Converting Enzyme-2 of Shorter Molecular Size to Target the Kidney Renin Angiotensin System

Wysocki, Jan; Schulze, Arndt; Batlle, Daniel

The two active short proteins 1-619 and 1-605 were then purified and their in vivo effects were compared with the native rACE2 and the half-lives of the injected recombinant proteins were evaluated ( Figure 6 ; Tables 1 and 2 ). Compared to the native rACE2 s blood half-life of 1.4 h after i.v. administration, ACE2 1-619 and 1-605 had a substantially extended half-life of around 4 h. In addition, the area under the curve for the short ACE2 proteins was about 4-5-fold higher than that of the native rACE2 after i.v. injection (Table 1 ) and 2-3-fold higher after i.p. administration (Table 2) . It is also noteworthy that, with the same dose, the peak plasma ACE2 activity after the infusion of both short variants was substantially higher than that of native rACE2 (Figure 6 ), further suggesting a better pharmacological profile, as compared to the native rACE2 form. It should be noted, however, that this pharmacokinetic profile was based on ACE2 activity assessed against an artificial substrate. The catalytic efficiency towards the artificial substrate, likewise, was much higher than that of the native ACE2 ( Figure 5A ). In contrast, when the catalytic efficiency was assessed using the natural substrate, Ang II, then there were no significant differences between the short ACE2 variants and the native ACE2 ( Figure 5B ).