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April 21, 2003
Volume 81, Number 16
CENEAR 81 16 p. 54
ISSN 0009-2347

JACS AT 125
PEPTIDES ON DEMAND

Bruce Merrifield's 1963 paper paved the way for automated synthesis of peptides and proteins

REBECCA RAWLS

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AUTOMATED Merrifield adjusts an early version of his peptide synthesizer in this 1969 photo.
If Bruce Merrifield had been a better chemist at the start of his career in the late 1950s, chemistry might be quite different today. Merrifield, a biochemist working at what would become Rockefeller University in New York City, needed to synthesize the small peptide growth factors he was studying. Using the standard methods of the day, he recalls, "I found that I could make them, but it took a long time, yields were low, and a lot of things went wrong along the way. Of course, I was a rank amateur, and a real expert could have done it faster. But it seemed to me that there ought to be a better way to do the synthesis."

As Merrifield was soon to show, there was, indeed, a better way. In his classic 1963 paper in the Journal of the American Chemical Society [85, 2149 (1963)], he demonstrated that by covalently attaching the first amino acid of a desired peptide to a solid resin support, he could build the product peptide in a stepwise fashion on the solid support. At each step, he purified the product simply by washing away side products and excess reactants, all of which remained in solution. The method practically eliminated the tedious purification and repeated recrystallization steps of classic peptide synthesis. Perhaps more important, Merrifield's approach made it possible to get almost quantitative yields for each amino acid addition, greatly expanding the range of polypeptides and proteins accessible by chemical synthesis.

Conceptually, it's a small jump from Merrifield's stepwise high-yield synthesis of polypeptides to an automated procedure. In practice, it took Merrifield and his colleague, John Stewart, less than a year to design and build a peptide-synthesizing apparatus. Others soon applied the general approach to develop automated synthesis for nucleic acid polymers, as well.

Merrifield noted the possibility of automating his synthesis in his JACS paper, though not quite as explicitly as he had originally intended. One of the reviewers of the manuscript found mention of automation " 'regrettable,' meaning, he didn't believe a word of it," Merrifield recalls. "So I had to tone that down a little to get the paper published. I did mention it, but in a milder way."

Merrifield's method rapidly transformed the synthesis of polypeptides and oligonucleotides, and its importance was acknowledged in 1984 when he received the Nobel Prize in Chemistry. Yet a case could easily be made that the real impact of solid-phase synthesis on chemistry came later, when the technique began to be applied far beyond the synthesis of biopolymers. Stepwise solid-phase synthesis on resin supports is at the heart of combinatorial chemistry. It's also become a valuable tool in the synthesis of many complex natural products.

"One of the big revolutions in chemistry in the 1990s has been small-molecule synthesis in combinatorial libraries, or high-throughput parallel synthesis, using resin beads," notes Kim D. Janda, professor of chemistry at Scripps Research Institute. "A lot of this work is really grounded in Merrifield's initial paper."

"Today, complex organic molecules, including some of nature's most intriguing secondary metabolites, are being synthesized by solid-phase chemistry techniques that have their origins in the pioneering work Bruce Merrifield demonstrated 40 years ago with peptides," says K. C. Nicolaou, also a professor of chemistry at Scripps. Synthetic strategies using solid-phase synthesis have the added advantage that they can produce a valuable library of analogs in addition to the target molecule, he notes.

A new twist that chemists are exploring now is to attach catalysts for making small molecules onto resin beads. As in Merrifield's original application, attachment to a solid support greatly simplifies purification and, in this case, recovery of the catalyst.

"It's really the general principle, rather than the exact procedure, that's lasted," Merrifield notes. "Usually a methodology paper is good for two or three years; then someone comes up with a better method, and people forget about the first one. I've been lucky in that way."

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BUILDING PEPTIDES Merrifield's original synthesis attached protected amino acids to a growing peptide chain that was covalently bonded to a polystyrene bead. Saponification with sodium hydroxide released the final product from the bead.


C&EN is celebrating the 125th volume of the Journal of the American Chemical Society by featuring selected papers from among its 125 most cited. This paper was ranked fifth.

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Copyright © 2003 American Chemical Society



 
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