NEWS OF THE WEEK DRUG
DEVELOPMENT
comments chemistry and bio chemistry professor Gregg B. Fields of Florida Atlantic Uni versity, Boca Raton. Chemistry and biochemistry professor Laura L Kiesslingofthe University of Wisconsin, Madi son, notes that the Gryphon study ate SEP is also being used to de is one ofthefirst"to demonstrate velop other performance-en the practical benefits that can be hanced chemically synthesized attained by employing chemical proteins ofpotential clinical util synthesis to generate proteins with tailored activities.,, ity, Kochendoerfer says. Roche has agreed to pay Gry Kochendoerfer and coworkers phon as much as $155 million for synthesize SEP by making four exclusive worldwide rights to de peptides on a synthesizer, with velop, manufacture, and market modifications that make it possi SEP Ifclinical trials are successful, ble to combine the peptides and the drug could have an impact on attach polymer molecules to the approximately $7 billion an them. They make the precisionnual worldwide marketforEPO, length polymer by a solid-phase currently dominated by Amgen synthesis technique based in part andJohnson &Johnson. on one introduced in 1999 by EPO has recently caused trou Keith Rose, now chief scientific bling immune reactions in some officer ofGeneProt, Geneva, and patients. Kochendoerfer and a coworker. coworkers believe the polymer at The polymer molecules are tached to SEP might reduce such added site specifically to two of immune reactions. The polymer the peptides, using oxime-formalso protects the protein from ing ligation chemistry developed proteolytic attack and increases by Rose in 1994. The four pep its size, making it harderforthe tides are joined at cysteine residues kidney to clear it and thus allow using an approach developed in ing it to stay in the blood longer. 1994 by a group led by Stephen B. "SEP emphasizes a particular H. Kent, nowprofessor of chem strength of chemoselective liga istry and biochemistry at the Uni tion—the precise addition of versity of Chicago. The resulting modifying elements that signifi polypeptide chain is then folded, cantly improve the protein's cir and two disulfide bonds are culating half-life and hence the formed to generate the bioac tive protein's therapeutic potential," protein.-STU BORMAN
MADE FROM SCRATCH Protein conjugate made by total chemical synthesis improves on EPO
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PROTEIN CONJUGATE As
sembled 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 labora tory and modified with two mol ecules of a precision-length syn thetic polymer. EPO is a commercial protein drug used tofightanemia 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 some what variable composition. SEP was designed and synthe sized by agroup at GryphonTherapeutics, South San Francisco, led by Director of R&D Gerd G. Kochendoerfer and coworkers at the Blood Research Institute, Milwaukee[&*raa> 299,884(2003)}. The technology they used to cre
IN BRIEF: ACCOLADES The ACS Journal Archives last week re ceived the 2002 award for the "Best InternetBased Electronic Prod uct in Math/Science" from the Professional & Scholarly Publishing Division of the Asso ciation of American Publishers.
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Ρ Jl2 TOO Η 0 Ρ R-L-l-C-D-5-R-V-L-E-R-Y-L-L-E-A-K-E-A-E-K-l-T-T-G-C-A-E-l ;-H©5- L-N H Η HrA)[° Ε I O^NHO 0. E-V-A-Q-Q-G-V-E-M-R-K-W-A-Y-F-N-V-K-T-D-P-V-T-l-K V 0 T-R-C-A-E W Q-G-L-A-L-L-S-E-A-V-L-R-G-Q-A-L-L-V-K-S-S-Q-P G Τ 166 Y -s ο L L-A-R-L-L-T-T-L-5-R-L-G-S-V-A-K-D-V-H-L-Q-L-l Κ G L A Ώ 0 Q 0© Κ Q 0 ® ν / A R C H I T E C T U R E SEP sequence (left, with letter codes for amino acids) G R includes modified lysines (K, blue) where polymer molecules are attached, L F l-S-P-P-D-A-A-K-A-A-P-L cysteine peptide-ligation points (C, red circles), and disulfides (yellow). Two Ν R ligating cysteines are modified (green) to mimic glutamates in EPO. The polymer S-Y-V-R-F-L-K-R-F-T-D-A-T-l-T
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