I wrote here about "stapled peptides", which are small modified helical proteins. They've had their helices stabilized by good ol' organic synthesis, with artificial molecular bridging between the loops. There are several ways to do this, but they all seem to be directed towards the same end.
That end is something that acts like the original protein at its binding site, but acts more like a small molecule in absorption, metabolism, and distribution. Bridging those two worlds is a very worthwhile goal indeed. We know of hordes of useful proteins, ranging from small hormones to large growth factors, that would be useful drugs if we could dose them without their being cleared quickly (or not making it into the bloodstream in the first place). Oral dosing is the hardest thing to arrange. The gut is a very hostile place for proteins - there's a lot of very highly developed machinery in there devoted to ripping everything apart. Your intestines will not distinguish the live-saving protein ligand you just took from the protein in a burrito, and will act accordingly. And even if you give things intravenously, as is done with the protein drugs that have actually made it to clinical use (insulin, EPO, etc.), getting their half-lives up to standard can be a real challenge.
So the field of chemically modified peptides and proteins is a big one, because the stakes are high. Finding small molecules that modulate protein-protein interactions is quite painful; if we could just skip that part, we'd be having a better time of it in this industry. There's an entire company (Aileron, just down the road from me) working on this idea, and many others besides. So, how's it going?
Well, this new paper will cause you to wonder about that. It's from groups in Australia and at Genentech, (Note: edited for proper credit here) and they get right down to it in the first paragraph:
Stabilized helical peptides are designed to mimic an α-helical structure through a constraint imposed by covalently linking two residues on the same helical face (e.g., residue i with i + 4). “Stapling” the peptide into a preformed helix might be expected to lower the energy barrier for binding by reducing entropic costs, with a concomitant increase in binding affinity. Additionally, stabilizing the peptide may reduce degradation by proteases and, in the case of hydrocarbon linkages, reportedly enhance transport into cells, thereby improving bioavailability and their potential as therapeutic agents. The findings we present here for the stapled BH3 peptide (BimSAHB), however, do not support these claims, particularly in regards to affinity and cell permeability.
They go on to detail their lack of cellular assay success with the reported stapled peptide, and suggest that this is due to lack of cell permeability. And since the non-stapled peptide control was just as effective on artificially permeabilized cells, they did more studies to try to figure out what the point of the whole business is. A detailed binding study showed that the stapled peptide had lower affinity for its targets, with slower on-rates and faster off-rates. X-ray crystallography suggested that the modifying the peptide disrupted several important interactions.
Update: After reading the comments so far, I want to emphasize that this paper, as far as I can see, is using the exact same stapled peptide as was used in the previous work. So this isn't just a case of a new system behaving differently; this seems to be the same system not behaving the way that it was reported to.
The entire "staple a peptide to make it a better version of itself" idea comes in for some criticism, too:
Our findings recapitulate earlier observations that stapling of peptides to enforce helicity does not necessarily impart enhanced binding affinity for target proteins and support the notion that interactions between the staple and target protein may be required for high affinity interactions in some circumstances.19 Thus, the design of stapled peptides should consider how the staple might interact with both the target and the rest of the peptide, and particularly in the latter case whether its introduction might disrupt otherwise stabilizing interactions.
That would be more in line with my own intuition, for what it's worth, which is that making such changes to a peptide helix would turn it into another molecule entirely, rather than (necessarily) making it into an enhanced version of what it was before. Unfortunately, at least in this case, this new molecule doesn't seem to have any advantages over the original, at least in the hands of the Genentech group. This is, as they say, very much in contrast to the earlier reports. How to resolve the discrepancies? And how to factor in that Roche has a deal with Aileron for stapled-peptide technology, and this very article is (partly) from Genentech, now a part of Roche? A great deal of dust has just been stirred up; watching it settle will be interesting. . .