Albert Lasker
Clinical Medical Research Award

Award Description

David Cushman and Miguel Ondetti
For developing an innovative approach to drug design based on protein structure and using it to create the ACE inhibitors: powerful oral agents for the treatment of high blood pressure, heart failure, and diabetic kidney disease.

David Cushman and Miguel Ondetti Like true love, the course of truly pathbreaking biomedical research seldom runs smooth, but persistence and commitment do pay off. The story of the long, productive collaboration between David Cushman, a biochemist, and Miguel Ondetti, a chemist, is a remarkable tale of the ups and down of experimental science which, in this case, ends on a high note with the design of an important new class of drugs for hypertension and congestive heart failure.

Cushman and Ondetti share the 1999 Albert Lasker Award in Clinical Medical Research for the discovery and development of captopril, the first orally active ACE inhibitor—the parent drug to what is today a pharmaceutical treasure trove of newer drugs in cardiovascular medicine.

"It would not be an exaggeration to say that when we started collaborating in the identification of angiotensin converting enzyme (ACE) inhibitors in the late 1960s, we had no idea of the impact that our work would eventually have on the study and management of cardiovascular diseases," said Cushman and Ondetti a decade ago as they reviewed their work.

But it would be misleading to suggest that their accomplishments were the result of serendipity or good luck. In truth, their story is a prescient illustration of "rational drug design," a concept that is much heralded today as something made possible by computer imaging and genome science. But in the late 1960s and early 1970s, when the Cushman-Ondetti story begins, they pursued rational drug design with little more than a clear idea, open minds, and what Cushman calls, "straightforward, simple, chemical thinking."

Cushman and Ondetti have spent their professional lives at what is now the Bristol-Myers Squibb Pharmaceutical Research Institute in New Brunswick and Princeton, New Jersey. In the 1960s, ACE, which forms the hypertensive peptide angiotensin II from an inactive precursor angiotensin I, was recognized as a potential player in blood pressure regulation, but there were no good assays for characterizing either the enzyme or agents that inhibit its capacity to raise blood pressure.

Cushman, who received his Ph.D. from the University of Illinois, Urbana in 1966, joined the Squibb Institute in 1968 where, after unsuccessfully attempting to isolate plant enzymes, he developed the first quantitative assay for ACE and purified and characterized the enzyme.

Ondetti, a 1957 graduate of the University of Buenos Aires School of Sciences, was studying the chemical properties of natural products from plants at a Squibb outpost in Argentina when he was offered a position at the Institute's main laboratory in New Jersey. There, he joined a laboratory devoted to peptide synthesis.

"Because peptides are the natural messengers of the body, peptides were expected to lead to very specific drugs with few side effects," Ondetti observes. "Changes in a single amino acid in a peptide sequence can produce significant changes in a peptide's behavior, showing how finely tuned biological activity can be."

A seminar in 1968 by Sir John Vane, a scientific consultant to Squibb, was the seminal event that led to the Cushman-Ondetti collaboration. Vane, who directed a laboratory at the Royal College of Surgeons in London, reported that peptides extracted from the venom of a Brazilian viper, Bothrops jararaca, by his co-worker, the Brazilian pharmacologist Sergio Ferreira, inhibit ACE, thus preventing formation of the hypertensive peptide angiotensin II. (This might play some role in enhancing the lethal action of the snake's venom, which kills quickly by causing a rapid, catastrophic plunge in blood pressure.)

The challenge to the Squibb researchers was clear: utilize the ACE assay to isolate and determine amino acid sequences of these snake venom peptides with an eye to new drug development.

Within a couple of years Cushman and Ondetti had isolated several peptides including a nine-amino-acid peptide, teprotide. They synthesized teprotide, and with colleagues at Squibb moved quickly into animal trials and then human studies of teprotide as an ACE inhibitor and anti-hypertensive drug.

The project was both a success and a failure. Teprotide was an effective ACE inhibitor, but it also was a large molecule—too large to be absorbed when given orally. Although it did lower blood pressure in hypertensive patients who received the drug by injection, proving once and for all the medical utility of ACE inhibitors, its widespread medical value was plainly limited because it could not be administered orally. Much had been learned, but the project was shelved.

Then, in 1974, Cushman read a paper in the journal Biochemistry that described a new potent and specific inhibitor of carboxypeptidase A, an enzyme that is important in the gastrointestinal system. Cushman and Ondetti immediately saw that it might be possible to design an analogous simple chemical compound that might be a specific inhibitor of ACE, which they felt sure was an enzyme very similar in structure to the much better characterized carboxypeptidase A. Using this new approach as a path back to their own "shelved" research, Cushman and Ondetti began again.

This time they took a different approach that proved essential to their subsequent success. Instead of concentrating on the structure of agents that could inhibit ACE, they directed their attention to the structure of the angiotensin converting enzyme—a structure that was not actually known, but which had been hypothesized on the basis of its probable similarity to carboxypeptidase A.

"Although understanding the relationship between the structure of teprotide and its biological activity was important to the eventual development of captopril, the key point of our new design strategy was the shift in focus from the inhibitor to the enzyme," Cushman and Ondetti observed. They began constructing agents that because of their molecular structures were likely to bind to the active site on ACE in a manner similar to the binding of the potent inhibitor of the analogous enzyme carboxypeptidase A.

Several interactions were proposed between ACE and the new class of inhibitors. The most important turned out to be interaction of a group on the inhibitor with the zinc ion proposed at the active site of ACE. Captopril, the final result of this process, contains a sulfhydryl group properly positioned to interact with the zinc of ACE, thereby guaranteeing the drug's efficacy.

Equally important, captopril is a small, orally active compound, easily absorbed into the bloodstream and therefore an ideal drug. Captopril entered clinical trials in 1977 and was approved by the Food and Drug Administration in 1981.

Although newer drugs have come along, the basic chemistry that led to captopril remains the underpinning of virtually all ACE inhibitors. They are now used not only for patients with hypertension or congestive heart failure but also play a role in treating kidney disease in diabetics and play a protective role in patients with progressive renal failure.

Looking back on the invention of captopril, Cushman and Ondetti draw interesting lessons about success and failure in science. It is obvious that they approached drug design in an entirely "rational" way. They note, "Many other approaches to drug development that appeared equally rational have ended in failure. As chemists and biologists dig deeply into the mechanisms of different diseases, they often follow the approach we used, and they often fail, sometimes because the 'rationale' is wrong and sometimes because they do not pursue it long enough. It has been our good luck to have collaborated on one that worked."