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Anemia Drug EPO Made by Chemists, Not Cells

Using chemical reactions to synthesize complex protein drugs could help researchers create more effective medicines.
December 13, 2013

Most drugs are simple, small molecules produced through well-defined chemical reactions: aspirin, Lipitor, and Prozac are made this way. Biotech drugs, on the other hand, are lab-made versions of human proteins such as insulin, and they are produced by living cells. This method of production can make it hard to identify the most potent versions of the compounds, because cells don’t produce identical copies. It also hinders researchers wanting to explore unique version of biotech compounds that cells don’t naturally make.

But a study published on Thursday in Science may help scientists overcome some of these limitations. Building on recent advances in peptide synthesis, scientists at the Sloan-Kettering Institute for Cancer Research in New York report that they have used chemical reactions alone to produce a biologic drug called erythropoietin. The work lays the foundation for chemists to create and identify other biologic compounds that could be more stable or potent than conventionally produced versions or have fewer side effects, says Richard DiMarchi, a biochemist at Indiana University in Bloomington.

Erythropoietin, or EPO, boosts production of red blood cells and is used to treat anemia, which is often caused by cancer, chemotherapy, or kidney failure. One of the original and most successful biotech drugs, EPO is a complex protein with chains of sugars on its surface. Chinese hamster ovary cells, a type of mammalian cells often used in biotech manufacturing, are generally used to produce a humanlike version of EPO for pharmaceutical use. Like many other complex biotech drugs, EPO must be produced in mammalian cells because microbes like bacteria and yeast don’t have the cellular machinery to stick the critical sugar chains onto the protein.

A given dose of EPO can contain hundreds of different versions of the protein with different sugar modifications, says Samuel Danishefsky, senior author on the study. Pure samples of EPO that contain only one version, such as the one reported by Danishefsky, could potentially allow researchers to identify more potent or safer versions of the drug, experts say.  

The work is not going to stop biotech companies from using cells to produce medicines, at least not any time soon. “It’s unlikely that chemical synthesis [of complex proteins] is going to be cost effective,” says DiMarchi. “But the fact that you now have that chemistry in a research laboratory allows you to [test] molecules with structural diversity that nature doesn’t provide.”

That means researchers could develop biologic compounds with potentially therapeutic components that cells don’t typically have. An amino acid that is not normally part of the toolbox used by human cells, for example, could help create a much more stable medicine. Once such a compound is discovered and shown to be helpful, researchers could then modify cells to perform the unnatural task.

“We are not trying to suggest that we are going to put recombinant biology out of business,” says Danishefsky, referring to molecular biology techniques used to modify cells so that they make biologic drugs. “But we can make things that recombinant technology can’t.” 

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