The
N- and C-terminal domains of human somatic angiotensin I converting
enzyme (sACE-1) demonstrate distinct physiological functions, with
resulting interest in the development of domain-selective inhibitors
for specific therapeutic applications. Herein, the activity of lisinopril-coupled
transition metal chelates was tested for both reversible binding and
irreversible catalytic inactivation of each domain of sACE-1. C/N domain binding
selectivity ratios ranged from 1 to 350, while rates of irreversible
catalytic inactivation of the N- and C-domains were found to be significantly
greater for the N-domain, suggesting a more optimal orientation of
M–chelate–lisinopril complexes within the active site
of the N-domain of sACE-1. Finally, the combined effect of binding
selectivity and inactivation selectivity was assessed for each catalyst
(double-filter selectivity factors), and several catalysts were found
to cause domain-selective catalytic inactivation. The results of this
study demonstrate the ability to optimize the target selectivity of
catalytic metallopeptides through both binding and catalytic factors
(double-filter effect)