California Researchers Investigate Antibody-like Viral Protein

September 27, 2005

Pharmaceutical Executive

Pharmaceutical Executive, Pharmaceutical Executive-09-27-2005, Volume 0, Issue 0

Scientists talk about the medical applications of a protein with 10 trillion possible functional variations. The molecule, present in viruses that infect bacteria, is the closest thing to an antibody ever discovered. And it might be easier to replicate.

A viral protein that can change its surface structure and selectively bind to bacterial surface proteins may be a candidate for new biological therapies.

    Two teams of California scientists studying the protein, which is called major tropism determinant (Mtd), believe the biotech industry can harness their discovery to target specific cells.

    Several years ago, a research team at University of California Los Angeles discovered that Mtd’s 10 trillion different configurations allow it to bind to bacterial surface proteins, which can change with every generation. In this respect, it is similar to an antibody.

    Working with a lab at the University of California San Diego, the researchers recently discovered that the viral protein has a much more stable structure than do antibodies, explained lead investigator, said Jeff Miller, professor of microbiology, immunology and molecular genetics at UCLA’s medical school. This makes it a viable candidate for clinical applications.

    Antibodies can generate more than 100 trillion configurations, but a looping structure in the protein can make it difficult to replicate the folds of the molecule in a lab, explained co-lead investigator Partho Ghosh, associate professor of chemistry and biochemistry at UCSD. Even in the body, this type of mis-folding can lead to diseases like light chain amyloidosis, which causes a build-up of mis-folded, sometimes mutated proteins on organ cells, commonly the kidney, heart or liver. This results in organ failure and death. 

    Mtd is stable in comparison to an antibody, because all 10 trillion variations result from changes in only 12 sites on the basic “scaffold” of the protein. This makes Mtd easier to manipulate for drug development purposes than antibodies. Ghosh predicted that all 10 trillion varieties of the Mtd protein would be able to bind to a target molecule.

    The molecule’s diversity is generated when the gene for Mtd is transcribed from DNA into messenger RNA, explained Miller, Instead of leaving the nucleus to be translated into protein, one segment of the mRNA is transcribed back into DNA by reverse transcriptase. During this process, “mistakes” are made in 12 vulnerable sites. These mistakes generate diversity when the genes are finally translated into protein.

    Each variant of the Mtd protein can potentially bind to a bacterial surface molecule. Ghosh and Miller believe that if this ability to generate diversity can be harnessed, it can be used to develop new therapies.

    Miller suggested that an engineered version of a bacteriophage, or bacterial virus, containing Mtd might be used as an antimicrobial. He also mentioned the possibility of using the Mtd diversity generator to develop protein-based therapies that can bind to targets of interest.

    Ghosh said inserting Mtd into bacteria, such as Escherichia coli, would produce a number of variants, which scientists could then “pan” for a version that binds to a specific target molecule. Once found, they could isolate the E. coli that produce the desired variant and amplify production.

    Mtd variants can be generated to identify and bind to cancer markers, Ghosh predicted. He also speculates that they may target highly infectious bacteria, such as anthrax, which can be used as weapons.

    Less than a year ago, Miller founded a biotech company, AvidBiotics with David Martin, a former vice president of research and development at Genentech.

    Martin said that AvidBiotics’ latest application of Miller’s diversity generator is engineering molecules to combat antibiotic-resistant bacteria. The engineered molecule will attack a resistant bacterium by binding specifically to one of the surface proteins that is not targeted by antibodies or existing drugs. AvidBiotics calls such attack molecules avidocins.

    In the future, AvidBiotics might use this technology to engineer diagnostic and industrial enzymes.

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