Potent new inhibitors of human renin

Abstract

The renal acid protease renin selectively cleaves its plasma substrate angiotensinogen to release the decapeptide angiotensin I, which in turn is cleaved by a carboxydipeptidase converting enzyme to yield the pressor octapeptide angiotensin II¹. It is generally accepted that the renin–angiotensin system has a physiological role in blood pressure and electrolyte homeostasis², and that abnormalities of the system contribute to certain forms of hypertension³. We previously showed that reduction of the Leu¹⁰–Leu¹¹ scissile peptide bond in the (6–13) octapeptide sequence 2 of equine angiotensinogen produced potent and selective inhibitors of canine plasma renin⁵. We have now used the same approach to modify the recently elucidated N-terminal sequence⁶ of human angiotensinogen and report here the production of highly active and species-specific in vitro inhibitors of endogenous human renin cleaving renin substrate in human plasma. Whereas the (6–13) octapeptide H-112 of human angiotensinogen is only a weak inhibitor of human plasma renin (IC₅₀ = 313 µM), the analogue H-113, in which the scissile Leu–Val bond has been reduced, has IC₅₀ = 0.19 µM. Extension of H-113 with Pro at the N-terminus and with Lys at the C-terminus⁷, giving the decapeptide derivative H-142, increases inhibitory potency further (IC₅₀ = 10 nM). We believe that the high in vitro inhibitory potencies of H-113 and H-142 are due to the ability of the reduced moiety —CH₂—NH— to act as a non-hydrolysable analogue of the tetrahedral transition state formed during hydrolysis of the (10–11) peptide bond. H-113 and H-142 are strongly species specific, and are highly specific for renin among acid proteases: H-142 has no inhibitory effect in vitro on human cathepsin D or renal acid protease at a concentration of 712 µM.