New Method Creates Proteins for Drug Development

Biochemists have discovered a process by which a simple organism can generate 10 trillion varieties of a single protein, a finding that may provide a new way to develop new drugs.

Scientists from the University of California, San Diego (UCSD; USA) describe in the October 2005 issue of the journal Nature Structural and Molecular Biology, the mechanism by which a virus that infects bacteria, called a bacteriophage (or phage), can produce an array of variants of a specific protein.

Because this level of protein diversity is very rare, recreating the process in the laboratory could give investigators a new tool to create therapeutic enzymes, vaccines, and other medically significant proteins. This is only the second type of massively variable protein ever discovered, explained Dr. Partho Ghosh, a professor of chemistry and biochemistry at UCSD who headed the research team.

Only antibodies have more variation than this protein in phage. However, the genetic mechanism used by the phage to generate this diversity is completely different from that used by animals to produce antibodies, and has the advantage of giving the protein greater stability. If we can learn from these organisms how to set up a system that churns out proteins with enormous variability, it may be possible to target these new proteins to specific cells to treat disease, said Stephen McMahon, a former postdoctoral fellow in Dr. Ghosh's. This idea has already been picked up by the biotech industry.

The task of the greatly variable phage protein is to attach the phage to the bacteria they infect. The phage predator protein fits into a prey protein on the bacteria like a three-dimensional puzzle piece. However, bacteria are constantly changing the proteins on their surface. To keep up with the erratic alterations in the prey protein, the phage must generate many different predator proteins for at least one to have a satisfactory fit.

In their article, the USCD investigators reported how by changing the amino acids at one or more of just 12 sites on the predator protein, the phage are able to generate 10 trillion proteins, each with the potential to bind to a different prey protein. This variability happens as DNA is being copied into the RNA blueprint for the protein. The sequence of DNA bases at the 12 sites has novel features that cause frequent errors to be made in the copying process. As a result, the RNA ends up specifying a different amino acid, and a protein with different structural and chemical characteristics is produced.

Antibodies are another kind of predator protein that must react to quickly evolving prey proteins, because microorganisms are continually changing proteins on their surfaces to elude the immune system. Dissimilar from the phage protein, antibodies have a complex loop structure. The size of the loops differs in addition to the amino acid building blocks that make up the antibody protein. Even though this process can generate more than 100 trillion different antibodies, the scientists stated that replicating it in a test tube would be very difficult because the loops would have the propensity to fold improperly.

Because of its stability, the phage protein makes a better model to create protein diversity in a test tube, explained Jason Miller, a graduate student in Dr. Ghosh's lab who performed much of the research. Our discovery shows that nature has provided at least two completely different methods to generate a huge amount of protein variability, and it opens up a whole new platform for protein development.



Related Links:
University of California, San Diego