ANGIOTENSIN-CONVERTING ENZYME INHIBITORS

Angiotensin-converting enzyme (ACE) converts the biologically inactive peptide angiotensin I to angiotensin II, a highly active component in the complex biochemical system for regulating blood pressure. Some individuals develop imbalances in this system that lead to hypertension, an important medical issue that affects one in three adults at some time in their lives. The health care costs associated with hypertension were $13.7 billion in 1991.

Following the isolation of these two peptides in the United States, scientists in Brazil and Japan discovered a series of peptides in snake venoms that lowered blood pressure in people. These seemingly unrelated studies were linked when biochemists purified ACE and found that ACE is inhibited by these same snake-venom peptides—inhibitors of ACE apparently restore the balance to the system that regulates blood pressure. The stage was then set for the use of the snake-venom peptides as a starting point for the design and synthesis of clinically useful inhibitors of ACE. The development of these drugs has had an important influence on the treatment of both hypertension and chronic heart failure.

The ACE-inhibitor problem. Because the 3-dimensional structure of angiotensin-converting enzyme has not been fully determined, computational chemists have studied the related protein thermolysin. This computer-generated image depicts the binding of an inhibitor (red-orange) to thermolysin.

Scientists discovered that zinc is a key component in the ACE enzyme. This discovery allowed them to deduce molecular properties that could permit inhibition of the enzyme's activity. Combining this information with knowledge of the snake-venom inhibitors, chemists designed and synthesized the inhibitor captopril and demonstrated its ability to lower blood pressure in animals and in humans. Because occasional human side effects such as rashes and loss of taste were reminiscent of those from penicillamine, chemists suspected that the similarities resulted from specific sulfur atoms that are common to both molecules. A worldwide search began for a new inhibitor that would retain both the zinc-binding ability and the biological activity. Chemists found an ingenious solution to this problem by accepting a partial loss of potency from replacement of a key sulfur atom that was offset by the potency-increasing effect of modifying another portion of the molecule that enhances its binding to the ACE molecule. The end result was the highly effective inhibitor, enalapril.

All in all, the ACE story is a beautiful illustration of successful interaction among chemists, biochemists, and biologists in both academic and industrial environments. It set the stage for the discovery of other highly specific enzyme inhibitors such as lovastatin, which effectively and safely lowers cholesterol levels.



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