Inhibitors of renin: present and future

Four classes of compounds have been demonstrated to be renin inhibitors of high potency: specific antibody, general peptide inhibitors of acid proteases, analogs of angiotensinogen and peptides that are related to the amino-terminal sequence of renin's precursor (Pro-renin). With the purification of renin, specific polyclonal or monoclonal antibodies have become available. The former have already been used extensively in physiologic studies in intact animals. Pepstatin is an inhibitor of many acid proteases. Its in vivo application has been retarded by its relative insolubility, but recent chemical modifications, particularly the addition of charged amino acids at the carboxy-terminus have rendered it more useful. The minimal substrate for renin is an octapeptide segment of the protein substrate: His-Pro-Phe-His-Leu-Leu-Val-Tyr. Variants of this sequence have resulted in competitive inhibitors that are useful in vivo. Recently, remarkably active inhibitors have been synthesized by reducing the peptide bond that is cleaved by renin, producing what may be a transition state inhibitor. Several of these peptides have been shown to be effective as in vivo inhibitors of the hypertensive effect of the enzyme. The development of inhibitors based on Pro-renin sequences are awaited with interest.