The power of proteins – a brief history
By the turn of the 20th century, most of the 20 common amino acids that form the protein “backbone” had been discovered. Scientists also had identified certain proteins, called enzymes, that could catalyze chemical reactions, and others, called antibodies, that could stimulate the body’s immune response to foreign “antigens.”
A groundbreaking discovery in 1922 demonstrated the unique power of proteins. That year, Canadian researchers used a purified extract of insulin, which they had isolated from the pancreas, to save the life of a 14-year-old diabetic boy. Within a year, the manufactured protein became available worldwide. For the first time in history, there was an effective treatment for diabetes.
In the early 1970s, a succession of key developments in genetics and immunology opened the door to protein therapeutics. The ability to transplant genes between different species led to the development and marketing of the first genetically engineered drug, human insulin, in 1982, followed by human growth hormone in 1985, and the first genetically engineered vaccine, to fight hepatitis B, in 1986.
Nine years earlier, in 1975, British researchers Georges Köhler and César Milstein figured out a way to fuse antibody-producing cells from immunized mice with antibody-secreting mouse cells derived from a type of cancer called myeloma. The result was a “hybridoma,” a line of hybrid cells that could be grown indefinitely and, when injected into mice, could produce large amounts of “monoclonal” antibodies, mass-produced to recognize a specific molecular target.
Genetic engineering techniques were used to “humanize” the mouse antibodies so they were less likely to be rejected by the body’s immune system. Since 1986, the U.S. Food and Drug Administration has approved 11 monoclonal antibodies, primarily to prevent rejection of transplanted organs and combat cancer. Herceptin, approved in 1998, is a monoclonal antibody used in the treatment of breast cancer.
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.
Director, Vanderbilt Institute of Chemical Biology
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.