The power of proteins a brief history  pg. 2

Technological advances and the urgency of the AIDS epidemic led to a new field in the early 1990s – the design of drugs based on the three-dimensional structure of target proteins. The first drugs to come out of this drug-design pipeline were the protease inhibitors, which block an enzyme used by the AIDS virus to make infectious copies of itself.

In combination with other drugs, protease inhibitors can reduce the AIDS virus to undetectable levels in the blood, and they have substantially increased survival rates.

The identification of the two cyclooxygenase (COX) enzymes is another example of the power of proteins. The enzymes produce prostaglandins, fatty-acid molecules that exert a wide range of effects, from wound healing to inflammation to blood clot formation to promoting cancer growth.

Larry Marnett, Ph.D.
Director, Vanderbilt Institute of Chemical Biology
Photo by Dean Dixon
Prostaglandin production by one of the enzymes, called COX-1, protects the stomach lining, whereas activation in other tissues of a related enzyme, COX-2, can lead to inflammation, pain and tumor growth.

This finding led to the development and the marketing of the blockbuster arthritis drugs Celebrex and Vioxx, which specifically inhibit the COX-2 enzyme without affecting the activity of COX-1. Their ability to discriminate between the two COX enzymes means they can relieve pain and inflammation without causing stomach upset and ulcers, a problem with other non-steroidal, anti-inflammatory drugs that block both enzymes. Celebrex and Vioxx also are being tested at Vanderbilt and elsewhere for their potential to prevent colorectal cancer.

This is only the beginning, says Lawrence Marnett, Ph.D., director of the Vanderbilt Institute of Chemical Biology. Marnett and his colleagues have been studying the three-dimensional structure of the COX enzymes with an eye to developing new and more effective drugs to inhibit them. “The building ‘tsunami’ of information about the structure and function of proteins is going to have a major impact on drug design,” he predicts.

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