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 t...

Source: In the Pipeline - February 24, 2014 Category: Chemists Tags: Chemical Biology Source Type: blogs