NEWS OF THE WEEK
ROCHE DECISION REVERBATES PHARMACEUTICALS: Drug firm’s exit from RNAi space hits Alnylam, Tekmira
OCHE’S DECISION to abandon RNAi drug
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Alnylam’s Cambridge labs lost a research contract with Roche.
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research as part of extensive cuts across its business has investors worried that enthusiasm for the gene-silencing technique is waning. Shares of Alnylam and Tekmira, two leading RNAi technology firms, tumbled on the news. After investing more than $500 million in less than three years to assemble an RNAi research effort, Roche is shutting down RNAi R&D at sites in Kulmbach, Germany; Madison, Wis.; and Nutley, N.J. (C&EN, Nov. 22, page 6). Cambridge, Mass.-based Alnylam was the hardest hit by the news. In 2007, Roche handed Alnylam $331 million in a broad research pact covering RNAi drugs. The deal included the purchase of the Kulmbach site, which became Roche’s “center of excellence”
IN SEARCH OF CYSTEINES CHEMICAL BIOLOGY: New technique finds superreactive cysteines in proteins YSTEINE’S HIGH POTENTIAL for nucleophilic-
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ity makes the amino acid a potent site of reactivity in proteins, but researchers find it hard to assess the reactivity of a given cysteine side chain in a sea of proteins of unknown function. Now, researchers led by Benjamin F. Cravatt III at Scripps Research Institute, La Jolla, Calif., have reported an approach to obtain a proteome-wide assessment of cysteine reactivity. The identification of hyperreactive cysteine sites is O
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TAG, YOU’RE IT Proteins that have exposed cysteines react with iodoacetamide probe.
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for RNAi research. Alnylam received a nice chunk of funding each year from Roche. Last year, for example, it reported $57 million in research revenues from the collaboration. It also would have enjoyed royalties on any drug that reached the market. For Alnylam, the setback comes just weeks after Novartis declined to opt in to a technology licensing clause in a five-year research pact. Novartis’ decision cost Alnylam a $100 million payment, and the biotech firm subsequently said it would cut 25–30% of its employees. Tekmira, meanwhile, loses out on a licensing deal signed just last year. Roche paid $18.4 million to formulate its RNAi products using Tekmira’s lipid nanoparticle delivery technology. Roche expected the pact would enable it to put its first RNAi-based drug into human studies by the end of this year. Despite the bad news for RNAi, industry observers are not convinced that the drug industry has given up on the technology. “We believe this was a move that had mainly to do with internal resource allocation decisions and not a reflection on the progress made by Roche or their confidence in the space,” says Simos Simeonidis, a stock analyst with Rodman & Renshaw. In his view, the company made cuts in technology areas where spending was high but commercial products were still years away.—LISA JARVIS
an important accomplishment because modification of cysteine residues—by oxidation, for example—can override posttranslational cues such as phosphorylation that results in activation, inactivation, or changes in stability of some proteins, comments Cristina M. Furdui of Wake Forest University School of Medicine. Cravatt’s technique first exposes proteins to a probe with an electrophilic iodoacetamide that reacts with non-disulfide-bonded cysteines and an alkyne handle for easy isolation. After the probe has a chance to react with exposed cysteines, the protein sample is chopped up by enzymes (Nature, DOI: 10.1038/nature09472). The probes, now with a reactive cysteine attached, are recovered using azide-alkyne Huisgen cycloaddition by means of the probe’s alkyne handle. Using mass spectrometry and an isotopically labeled sample, the team can thus predict functional, reactive cysteines in proteomes. The team tested its technique on cancer cell proteomes, as well as a group of 12 proteins engineered to employ reactive cysteines. The technique succeeded in picking out the only two proteins in this collection whose engineered cysteines are catalytically active. “The potential utility for this approach is great, such as for sifting through proteomes and identifying proteins or sites of special reactivity,” comments Leslie B. Poole, a biochemist at Wake Forest University. Next up, Cravatt’s team aims to better understand the function of hyperreactive cysteines in proteins of unknown function or implicated in diseases such as cancer and neurodegeneration.—SARAH EVERTS
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