1
13 WWW.CEN-ONLINE.ORG MARCH 1, 2010 A NEW WAY TO synthesize snail-based peptides called α-conotoxins, fold them into their na- tive structures, and screen them for biological activity has been developed by an Australian research group. The approach could lead to new medications for neurological disorders and other conditions. α-Conotoxins are one of many families of cono- toxins—neurotoxic peptides made by predatory cone snails, which use them to immobilize their prey. Cono- toxins have attracted considerable attention for their bioactivity, especially pain relief. One conotoxin, Prialt (ziconotide), is an approved drug for severe chronic pain, and a conotoxin analog called Xen2174 is in Phase II human clinical trials, also as a pain reliever. Although those two agents belong to other cono- toxin families, α-conotoxins also relieve pain. But it has been difficult to synthesize α-conotoxins in their natively folded forms to assess their prospects as drug candidates. The peptides each have two disulfide links, and when they are synthesized as linear peptides, their disulfide-forming cysteines often combine with the “wrong” cysteine partners, yielding nonnative, mis- folded α-conotoxins with impaired biological activity. Bioactive-peptide specialist Paul F. Alewood of the University of Queensland and coworkers have now found a workaround (J. Am. Chem. Soc., DOI: 10.1021/ ja910602h). They synthesize α-conotoxins in which one pair of cysteine residues has been replaced by a pair of selenocysteines. The seleno- cysteines combine to form diselenides more readily than cysteines react to form disulfides. So when a linear α-conotoxin is oxidized, the diselenide forms first, pre- venting mismatches, and the disulfide forms later, yielding a correct structure. The diselenide analogs generally have conforma- tions and bioactivities similar to those of the corre- sponding native α-conotoxins, and in some cases, the analogs’ bioactivities are better. Alewood and coworkers also report the first method for synthesizing selenocysteine analogs of α-conotoxins on solid-support beads and then folding them while they are still on the resin. Having the folded analogs on solid-support particles makes it possible to screen the compounds for biological activity more quickly and con- veniently than has been previously possible. The use of diselenides as disulfide replacements in synthetic peptides was pioneered in the late 1990s by bioorganic chemist Luis Moroder of the Max Planck Institute of Biochemistry, in Martinsried, Germany. But the technique has only recently been applied to conotoxins—in one earlier study by the Alewood group and in another by conotoxin specialist Grzegorz Bulaj of the University of Utah and coworkers. Of the new work, Bulaj says: “Having selenocono- toxins on-resin is a very nice advance. The solid- support-based approach can probably be extended to other disulfide-bridged peptides as well. It’s an impor- tant step toward the discovery and development of cysteine-rich peptides as future drugs.” —STU BORMAN A synthesized linear α-conotoxin can form disulfide bonds (yellow) in various ways, yielding different structures. BASF and Air Liquide are the chemical industry leaders in creating sustainable value, and Dow Chemical comes in last, a new study finds. The results of the study were com- piled by academics at Queen’s University Management School, in Belfast; France’s Euromed Management school, in Mar- seille; and the Institute for Future Studies & Technology Assessment, in Berlin. BASF provided financial support for the project. The study took data for AkzoNobel, Air Liquide, BASF, Bayer, Dow, DSM, DuPont, Reliance Industries, and Shell Chemicals in 13 sustainability-related categories such as R&D spending, number of em- ployees, worker accidents, and green- house gas emissions. The researchers determined how much of a company’s net operating cash flow is generated by one unit of each category. They measured the result against the weighted average for the entire group. The team of researchers then averaged the differences for all 13 categories to come up with a bottom-line figure dubbed “sustainable value,” which reflects broadly how efficiently companies are using resources. On the basis of 2007 data, BASF gen- erated the most sustainable value, and AkzoNobel, Dow, and DSM generated neg- ative sustainable values. Correcting for company size, however, Air Liquide comes in first, followed by BASF and Bayer. One of the report’s authors, Frank Figge of Queen’s University, says a goal was to make sustainability more intuitive for managers by putting it in monetary terms. “What we are trying to do here is to ac- count for resource use in the same way in which you would account for economic data or economic capital,” he tells C&EN. In a statement, Dow says the report doesn’t accurately assess the sustain- ability of a company, especially given the study’s categories and its use of cash flow to measure returns. “While no mea- suring system is perfect, this one falls well short of the standards to which we hold ourselves,” the company says. —ALEX TULLO RESOURCE USE New report says BASF creates the most sustainable value NEWS OF THE WEEK MARKUS MUTTENTHALER NEW WAY TO SCREEN α-CONOTOXINS DRUG DISCOVERY: Work could lead to medications based on these neuroactive peptides
