WASHINGTON - It's not quite duct tape, supposedly all that creative scientists truly need to keep their labs together. But at this week's annual meeting of the American Association for Cancer Research, scientists presented the next best technology for making new drugs: staple them.

Greg Verdine, professor of chemistry of Harvard University, presented the stapling technique in a plenary session talk on "Drugging the Undruggable." He said that "the term 'undruggable' applies a certainty beyond what is justified on scientific grounds."

Many targets are indeed undruggable with current technologies. Verdine estimated that "if you start with a new target today, there is a lower than 50 percent chance - and that is generously speaking - that any of them would give you a drug within a reasonable time frame."

But Verdine pointed out that what undruggables need are new technologies. And the stapling technology, which basically binds two amino acids in a peptide, is one such method.

Verdine began his lecture with a brief overview of why some targets are more difficult to hit than others. It's basically a mix of location and shape: Small molecules, he explained, are best for targets with hydrophobic pockets, whether those pockets are on the inside or outside of cells. In contrast, biologics such as antibodies can target flat surfaces as well as pockets. But because of their size, they are limited to targets on the cell surface.

Most of a biologic molecule does not, in fact, interact with the target. So theoretically, using just the part of the biologic that actually interacts with the target could improve biologics' ability to get into cells and target more different surfaces than small molecules once it is there.

The problem with that idea is that the rest of the protein stabilizes the part of interest - frequently an alpha helix, since roughly 40 percent of all protein-protein interactions involve alpha-helices. But when the alpha-helix is separated from the rest of the protein, more often than not "it is now a large ensemble of interconverting structures - on the nanosecond scale," Verdine explained. And most of those structures will be degraded rapidly by intracellular proteases - not that it matters for drug development purposes at that point, since misfolded, they rarely manage to enter cells in the first place and do not bind the target efficiently if they do.

Verdine described a method for stabilizing such peptides that get around this limitation: by replacing two of a peptide's amino acids with synthetic ones, and essentially stapling them together in a chemical reaction known as Ruthenium-catalyzed olefin metathesis, a method that netted its discoverers the 2005 Nobel Prize for Chemistry. (See BioWorld Today, Oct. 7, 2005.)

More generally, Verdine said that like small molecules, the stabilized alpha-helices "are fully synthetic. So every single atom can be addressed during the process of drug optimization. That's why I think of these as a new class of drugs."

Using the method, the gyrations of peptides could be reduced considerably; in one example, the p53 regulator hdm2, the researchers managed to generate a peptide that was in an alpha-helical conformation up to two-thirds of the time.

While it is currently not possible to predict in advance which two amino acids in any peptide should be tethered to give maximum stability, Verdine said his team still had to screen only a manageable number of molecules to find out empirically "because we are starting with Nature's cue" in form of the amino acid sequence.

Loren Walensky, a collaborator of Verdine's at the Dana-Farber Cancer Institute, presented data on using the stapling techniques to stabilize the apoptosis protein bid. Bid targets the proapoptotic protein Bcl-2, which Verdine referred to as "the poster child for undruggable targets." Bcl-2 does have a hydrophobic pocket, but it is so shallow that generating small molecules that would fit the pocket took 10 years and what Verdine called "Herculean effort."

The researchers managed to generate a stabilized Bid alpha-helix, which they first described in Science in 2004. At this year's AACR, Walensky presented data showing, among other things, that when they tested it in mice, it suppressed leukemia and increased survival in leukemic mice. Verdine said that they also have managed to generate stabilized alpha-helices to a number of other targets, including "some of the really frustrating targets, which have been undruggable for over a decade beyond the discovery that they are biologically important."

The stapling technique has been licensed to Boston start-up Renegade Pharmaceuticals, which Verdine owns stock in. The conference ends today.