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February 24, 2014
Another Round of Stapled Peptide Wrangling
When we last checked in on the Great Stapled Peptide Wars, researchers from Genentech, the Walter and Eliza Hall Institute and La Trobe University (the latter two in Australia) had questioned the usefulness and activity of several stapled Bim BH3 peptides. The original researchers (Walensky et al.) had then fired back strongly, pointing out that the criticisms seemed misdirected and directing the authors back to what they thought had been well-documented principles of working with such species.
Now the WEHI/Genentech/La Trobe group (Okamoto et al.) has responded, and it doesn't look like things are going to calm down any time soon. They'd made a lot of the 20-mer stapled peptide being inactive in cells, while the reply had been that yes, that's true, as you might have learned from reading the original papers again - it was the 21-mer that was active in cells. Okamoto and co-workers now say that they've confirmed this, but only in some cell lines - there are others for which the 21-mer is still inactive. What's more, they say that a modified but un-stapled 21-mer is just as active as the closed peptide, which suggests that the stapling might not be the key factor at all.
There's another glove thrown down (again). The earlier Genentech/WEHI/La Trobe paper had shown that the 20-mer had impaired binding to a range of Bcl target proteins. Walensky's team had replied that the 20-mer had been designed to have lower affinity, thus the poor binding results. But this new paper says that the 21-mer shows similarly poor binding behavior, so that can't be right, either.
This is a really short communication, and you get the impression that it was fired off as quickly as possible after the Walensky et al. rebuttal. There will, no doubt, be a reply. One aspect of it, I'm guessing, will be that contention about the unstapled peptide activity. I believe that the Walensky side of the argument have already shown that these substituted-but-unstapled peptides can show enhanced activity, probably due to cranking up their alpha-helical character (just not all the way to stapling them into that form). We shall see.
And this blowup reflects a lot of earlier dispute about Bcl, BAX/BAK peptides, and apoptosis in general. The WEHI group and others have been arguing out the details of these interactions in print for years, and this may be just another battlefield.
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