ABSTRACT
Angiotensin II is produced by a proteolytic cascade—known as the renin-angiotensin system—in which the aspartic proteinase renin catalyses the rate-limiting cleavage of angiotensinogen produced by the liver to yield the decapeptide angiotensin I. One enigmatic feature of renin is its extreme substrate specificity, its only known natural substrate being a single Leu-Val peptide bond of angiotensinogen. The availability of crystal structures of a number of renin inhibitors complexed with fungal aspartic proteinases allowed new compounds to be designed and modeled by such techniques as computer graphics, energy minimization, and molecular dynamics. Early efforts were made to improve the resistance of renin inhibitors to hydrolysis in vivo by the use of blocking groups at the N- and C-terminii and replacement of susceptible peptide bonds other than the renin cleavage site. The renin-inhibitor structures also make an important contribution towards the rational design of effective antihypertensive agents.
