Emily F. Sabo

Inhibition of angiotensin-coverting enzyme by analogs of peptides from Bothrops jararaca venom.

Nachweis mit Analogen der im Gifte vonBothrops jararaca gefundenen Peptide, dass die Inhihibition des Angiotensins «converting enzyme» von zwei eindeutigen Teilsequenzen dieser Peptide abhängig ist. Die hohe spezifische kompetitive Inhibition, hervorgerufen durch die Peptide vonBothrops jararaca, wird der Bindung ihrer Tripeptidreste vom Carboxyterminus mit dem aktiven Zentrum des Enzyms zugeschrieben, die in gleicher Weise wie die Peptidsubstrate mit dem Enzym gebunden werden. Die Wirksamkeit der Giftpeptide hängt von der Bindung eines zweiten Teiles der Peptide mit dem Enzym ab.

Design of new antihypertensive drugs: Potent and specific inhibitors of angiotensin-converting enzyme

Abstract The similarity of the biologically important enzyme angiotensin-converting enzyme to the structurally characterized digestive enzyme carboxypeptidase A has led us to develop a hypothetical model of the mechanism of binding of substrates to its active site. In this model, a positively charged group on the enzyme forms an ionic bond with the negatively charged carboxyl group of the substrate; a hydrogen bonding group of the enzyme binds with the terminal peptide bond of the substrate, and the tightly bound zinc ion of the enzyme binds to the penultimate (scissile) peptide bond of the substrate. Succinyl- l -proline (SQ 13,745) was synthesized as a potential inhibitor of angiotensin-converting enzyme by analogy to d -2-benzylsuccinic acid, an inhibitor of carboxypeptidase A; it was a moderately potent but specific inhibitor of the enzyme. Structure-activity studies carried out using the hypothetical model as a guide led to the synthesis of d -2-methyl-succinyl- l -proline (SQ 13,-297) and d -2-methylglutaryl- l -proline (SQ 14,-102), more potent inhibitors of the enzyme that were shown to be orally active in rats. Attempts to replace the zinc-binding carboxyl group of these compounds with groups with greater affinity for zinc have led to the synthesis of extremely potent inhibitors such as 3-mercapto-propanoyl- l -proline (SQ 13,863) and d -3-mercapto-2-methylpropanoyl- l -proline (SQ 14,225). The most active compound, SQ 14,225, is a purely competitive inhibitor of angiotensin-converting enzyme with an enzyme-inhibitor dissociation constant (Ki) of 1.7 × 10−9M. It is an extremely potent and specific inhibitor of angiotensin-converting enzyme and appears to have great potential for the treatment of hypertensive disease.

Development and design of specific inhibitors of angiotensin-converting enzyme

Captopril is a remarkably effective new antihypertensive drug designed and developed as a potent and specific inhibitor of angiotensin-converting enzyme, a zinc metallopeptidase that participates in the synthesis of a hypertensive peptide, angiotensin II, and in the degradation of a hypotensive peptide, bradykinin. Earlier studies with a snake venom peptide (teprotride or SQ 20881) that could be administered only by injection demonstrated that specific inhibitors of angiotensin-converting enzyme could be highly effective as antihypertensive drugs, and helped to clarify the specificity and mechanism of action of the enzyme. A hypothetical model of the active center of angiotensin-converting enzyme based on its presumed analogy to the well characterized zinc metallopeptidase carboxypeptidase A was used to guide logical sequential improvements of a weakly active prototype inhibitor that led eventually to the highly optimized structure of captopril. The hypothetical working model of the active site of angiotensin-converting enzyme used to develop captopril continues to provide a firm basis for development of new types of specific inhibitors of this biologically important enzyme.

Design of New Antihypertensive Drugs

Angiotensin-converting enzyme is one of the enzyme components of the renin-angiotensin system (Figure 1), the products of which play physiologically important roles in maintenance of cardiovascular homeostasis and contribute to the elevation of arterial blood pressure in various hypertensive disease states.1–4 The immediate product of the action of angiotensin-converting enzyme is the octapeptide, angiotensin II, the most potent naturally occurring pressor substance known. Angiotensin III, a hepta-peptide derived from a further enzymatic cleavage of angiotensin II, is a potent stimulator of secretion of aldosterone by the adrenal cortex.5 Angiotensin-converting enzyme also plays a biologically important role in the inactivation of the potent vasodepressor peptide bradykinin.6