|Stapled peptide. Image: Nature|
The simple thinking is that if you constrain a helix to its helical shape using various chemical strategies, you could minimize the entropic cost of helix formation. In addition, by modulating the properties of whatever chemical group you are using to constrain the structure, you could possibly get better affinity, cell penetration and stability. The strategies used have been varied, from olefin linkers to hydrocarbon linkers, and they have a long history. But stapled peptides have been especially noteworthy; the staple in this case is a short hydrocarbon linker connecting one residue to another a few angstroms away. Based on this idea, groups from Harvard launched a biotech startup named Aileron. Stapled peptides, it seemed were on a promising upward trajectory.
Except that nothing in biology is as simple as it seems. A recent report from groups in Australia and Genentech demonstrated that a previously promising stapled helix which inhibits the antiapoptotic protein Bim is not as potent as it seemed. The problems seem to lie with the fundamental helical structure of the molecule; the paper found that in adding the hydrocarbon staple, you are perturbing some productive intramolecular hydrogen bonding interactions between the residues, and this results in an unfavorable enthalpy of binding.
It's worth reading Carmen's piece not just for the science but for the potential conflict of personalities; science is a human game after all. In this case the conflict arises not only from the Australia/Genentech group's doubts about the original Harvard peptide but the Harvard group's contention that the Australia/Genentech team was in fact looking at the wrong peptide.
Hopefully the misunderstanding will be cleared soon but one thing is clear; this debate seems to be good for science. Constraining helices and other peptides is a completely legitimate way of thinking about improving drug potency and properties, but the devil is in the details. Whenever you put on a constraint you are going to subtly perturb the structure of the molecule, and what seems important here is to investigate how these subtleties will affect the desired functions and properties.
Ultimately stapled peptides are no different from a dozen other drug design strategies. There are cases where they will work and cases where they won't, and any efforts to tease these differences apart will advance the science. Neither stapled peptides nor any other kind of specific drug modification is going to give us the silver bullet. But we already knew this, didn't we?