Built-in drugs could target tissues.
Researchers at the Max Planck Institute for Biochemistry in Martinsried, Germany, demonstrated the feasibility of this idea by synthesizing a protein in which one amino acid was replaced with a non-natural, biologically active one. According to their scenario, the modified protein would travel inside the body like its normal counterpart and then deliver its drug--the nonstandard amino acid--to target cells. The team's report appears in the Jan. 20 Proceedings of the National Academy of Sciences.
"This is very nice work," says Peter G. Schultz of the University of California, Berkeley. "It's a novel application of the incorporation of amino acid analogs into proteins."
The researchers fed Escherichia coli bacteria with thiaproline, a version of the amino acid proline in which a sulfur atom replaces a carbon atom. About 20 years ago, thiaproline was heralded as a potential cancer treatment. "That euphoria calmed down a few years after," says study coauthor Nediljko Budisa, "mainly because of many toxic effects of thiaproline for other parts of the body."
Budisa and his coworkers had engineered the E. coli to make the human protein annexin V, "a good model protein, since its structure is well known and characterized, and purification is convenient and simple," Budisa says. Annexin V moves calcium ions across membranes, but its overall role in animals is not known.
The annexin V produced by E. coli incorporated thiaproline and retained its three-dimensional structure and biological function, but it was less stable when heated. Structurally familiar proteins should evade attack from the immune system while on their way to target cells, the authors reasoned. Once there, ordinary protein digestion should free up the altered amino acid to act as a drug.
Delivering pharmaceuticals in proteins could potentially reduce the amount of drug needed, suggests Budisa. Compared to the dose that achieves an effective overall concentration in the body, a much smaller amount of the compound could be escorted by a protein directly to appropriate tissues, where it would act, he says.
Amino acid substitution also provides a way to study how proteins fold and function. For example, scientists can deduce from the substitution of sulfur for carbon, an "atomic mutation," how that small difference affects annexin V.
This method comes with a catch, however. Bacterial synthesis produces a lot of protein, but the amino acids insert themselves randomly at many locations. Although that may be fine for drug delivery, protein studies require changes at a single location. Scientists would need to make the protein in a test tube, but then "you're limited to submilligram quantities," explains Schultz. To get around this obstacle, he and his colleagues are engineering a bacterium that can insert a non-natural amino acid only in specified locations.
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|Title Annotation:||placing drugs inside proteins may allow for the more specific targeting of conditions and tissues|
|Article Type:||Brief Article|
|Date:||Jan 24, 1998|
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