scale." The panel urges the U.S. to im bled peptide. This convergent coupling mediately initiate joint projects with follows a path developed for the solu tion phase by Peter T. Lansbury Jr. at Russia on both approaches. But Steve Fetter, professor of public Massachusetts Institute of Technology policy at the University of Maryland, [/. Am. Chem. Soc, 115,10531 (1993)]. College Park, believes the two options In the SKI approach, the first stage is are unrealistic, because Russia considers assembly of the oligosaccharide with its weapons plutonium a national trea one end anchored to a polystyrene sure to be saved as fuel for future breed bead through a silyl ether linkage. The er reactors. He suggests that the U.S. and free terminus is then converted to a Russia should work out a way for the 2-N-acetyl-l β-aminoglucosamine resi International Atomic Energy Agency to due. Coupling this residue to assem safeguard the plutonium weapons com bled peptides yields solid-phase-bound ponents in both nations. But there is lit glycopeptides. Removal from the sup tle chance the current Congress would port gives discrete glycopeptides in 20 approve such international controls. to 30% overall yield for 10 steps. Bette Hileman Beebe notes this synthesis deviates from solid-phase approaches pioneered by Horst Kunz of Johannes Gutenberg University in Mainz, Germany, Hans Paulsen of the University of Hamburg, A new method of solid-phase synthesis of pure entities from natural sources ex and Morten Meldal of the University of Copenhagen. Typically, she explains, glycopeptides—developed by scientists at tremely laborious. However, only a small part of a gly sugars or glycosylated amino acids are Sloan-Kettering Institute of Cancer Research (SKI), New York City—has coprotein is recognized by receptors, so added to a peptide assembled on a solid yielded some of the largest nitrogen- smaller synthetic mimics could be used support. linked glycopeptides ever prepared by in place of naturally occurring mole "The strategy is elegant and flexible completely chemical means. The meth cules. This prospect is fueling work on and allows the synthesis of various wellod may provide an efficient route to glycopeptide synthesis. defined glycopeptides to address their preparing pure samples of naturally The new method was developed by biological significance," says chemistry occurring glycoproteins. Columbia University chemistry profes professor Chi-Huey Wong of Scripps Glycoproteins take part in many bio sor Samuel J. Danishefsky, who also Research Institute, La Jolla, Calif. chemical processes. To study them, re holds an appointment at SKI, and by Wong also has come up with a solidsearchers must work with pure materi SKI postdoctoral fellows Jacques Y. phase method for glycopeptide syn als. But natural glycoproteins are struc Roberge and Xenia Beebe [Science, 269, thesis, but one that involves enzymes turally diverse. For example, the same 202 (1995)]. The team built an oligosac [/. Am. Chem. Soc, 116,1135 (1994)]. In peptide sequence can contain different charide on a solid polymer support Wong's approach, nucleoside-activated oligosaccharides, making isolation of and coupled it to a previously assem sugars are appended to solid-phasebound peptides through the enzyme glycosyl transferase. Another enzyme, protease, retrieves the product from the New glycopeptide synthesis uses solid-supported sugars solid support. Use of enzyme-mediated chemistry eliminates the need for pro tecting groups. ®-Q ο Both the SKI and Scripps methods al R H N ^ X X . Ser/Thr-R' low use of nonnatural amino acids and nonamino acids. But the SKI strategy is zo—A^o totally general in principle: It does not NHAc require use of transferases and nucleo Peptide containing Derivatized oligosaccharide side-activated hexoses. It can work with glycosylation site on solid support nonnatural (artificial) sugars. Coupling SKI's method allows the peptide por tion to be lengthened while the glyco peptide is still attached to the solid sup n port. Using this approach, the team has RHN^^JL x „ S e r / T h r _ R ' prepared trisaccharide tri- and penZO) ^ ^ O v Η (§)= solid support and linking group tapeptides and has extended a bound NHAc Τ R, R = peptide groups trisaccharide pentapeptide to a trisaccha Ο X = variable amino acid Ser/Thr = serine or threonine ride octapeptide. The researchers now N-linked glycopeptide Ζ = protecting group are pursuing their next goal: a glycopep Ac = acetyl tide with a mannose-rich carbohydrate. Maureen Rouhi ment of Energy to follow NAS's recom mendations and to pursue vitrification and MOX fuel options in tandem when DOE makes a final disposal decision ear ly next year. But neither approach can be pursued if Congress won't fund it. Indeed, many members of Congress favor developing advanced techniques such as accelerator-based conversion of plutonium into other elements. The pan el says these methods would impose "substantial additional costs, complexi ties, risks, and delays." However, Holdren stresses, the U.S. will not achieve its security objectives unless the Russians "carry out a disposi tion program in parallel on a similar time-
New method yields large N-linked glycopeptides
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