Human renin inhibitor peptides.

The discovery of angiotensin I converting enzyme inhibitors (ACEI) and of their efficiency in the treatment of high blood pressure and cardiac insufficiency constitutes one of the major advances in medicinal chemistry and therapeutics of the last decade. The design of captopril and its congeners resulted from a rational and systematic study of the interactions of carboxypeptidase A and angiotensin converting enzyme (ACE) with their substrates and inhibitors. Not only were ACEI found to be effective for treating high renindependent forms of hypertension, but unexpectedly, they were also active in normal and low renin hypertension. Very productive research on the ways of blocking the renin-angiotensin system has been undertaken by several academic and drug company laboratories with the aim of finding drugs that could be at least as potent but more selective. Indeed, long-term treatment by ACEI seems not to completely suppress the circulating renin-angiotensin system as plasma angiotensin II (Ang II) and aldosterone levels tend to return toward pretreatment values. In addition, ACE is not a specific enzyme in that it can hydrolyze substrates other than angiotensin I (Ang I), such as bradykinin, substance P, and enkephalins. The side effects observed with all ACEI, such as the rare cases of angioneurotic edema and the more frequent occurrence of cough, may be related to this lack of selectivity. It could be anticipated that potent and specific renin inhibitors would constitute an interesting alternative to ACEI for two reasons: 1) the first step in the renin-angiotensin system, the hydrolysis of angiotensinogen by renin, is rate limiting; and 2) renin has a unique specificity for angiotensinogen as there is no other known substrate for this enzyme. Research on renin inhibitors has been facilitated by the recent progress made on the molecular structures of renin and angiotensinogen and by the elucidation of the molecular mechanisms of action of aspartyl proteases and their inhibitors. Several other factors were apparently promising for the rapid design of a renin inhibitor: the discovery of pepstatin, a lead compound inhibiting the class of aspartyl proteases to which renin belongs; the use of simple biochemical assays for testing renin blockade; and the knowledge