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DRUG DEVELOPMENT
A protein conjugate assembled by total chemical synthesis could turn out to be the first completely synthetic protein-based compound to be developed as a commercial drug. The conjugate--synthetic erythropoiesis protein (SEP)--is a version of erythropoietin (EPO) that is assembled in the laboratory and modified with two molecules of a precision-length synthetic polymer. EPO is a commercial protein drug used to fight anemia caused by kidney disease, chemotherapy, and other conditions. SEP is as potent as EPO in mice and rats and remains active in the body two to three times longer. But SEP's structural composition is uniform, whereas commercial EPO is a recombinantly produced protein-sugar conjugate of somewhat variable composition. SEP was designed and synthesized by a group at Gryphon Therapeutics, South San Francisco, led by Director of R&D Gerd G. Kochendoerfer and coworkers at the Blood Research Institute, Milwaukee [Science, 299, 884 (2003)]. The technology they used to create SEP is also being used to develop other performance-enhanced chemically synthesized proteins of potential clinical utility, Kochendoerfer says. Roche has agreed to pay Gryphon as much as $155 million for exclusive worldwide rights to develop, manufacture, and market SEP. If clinical trials are successful, the drug could have an impact on the approximately $7 billion annual worldwide market for EPO, currently dominated by Amgen and Johnson & Johnson. EPO has recently caused troubling immune reactions in some patients. Kochendoerfer and coworkers believe the polymer attached to SEP might reduce such immune reactions. The polymer also protects the protein from proteolytic attack and increases its size, making it harder for the kidney to clear it and thus allowing it to stay in the blood longer. "SEP emphasizes a particular strength of chemoselective ligation--the precise addition of modifying elements that significantly improve the protein's circulating half-life and hence the protein's therapeutic potential," comments chemistry and biochemistry professor Gregg B. Fields of Florida Atlantic University, Boca Raton. Chemistry and biochemistry professor Laura L. Kiessling of the University of Wisconsin, Madison, notes that the Gryphon study is one of the first "to demonstrate the practical benefits that can be attained by employing chemical synthesis to generate proteins with tailored activities." Kochendoerfer and coworkers synthesize SEP by making four peptides on a synthesizer, with modifications that make it possible to combine the peptides and attach polymer molecules to them. They make the precision-length polymer by a solid-phase synthesis technique based in part on one introduced in 1999 by Keith Rose, now chief scientific officer of GeneProt, Geneva, and a coworker.
ARCHITECTURE SEP sequence (left, with letter codes for amino acids) includes modified lysines (K, blue) where polymer molecules are attached, cysteine peptide-ligation points (C, red circles), and disulfides (yellow). Two ligating cysteines are modified (green) to mimic glutamates in EPO. The polymer (right) is branched and negatively charged. SEP model (top right) shows branched polymer moieties (blue) and protein helices (red) and loops (green).
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