Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine . All content is Derek’s own, and he does not in any way speak for his employer.

Now here is something I didn’t expect: what may well be a completely new way to separate enantiomers, not based in any way on shape recognition versus another chiral substance.

[Quick background for those not in the field: a great many three-dimensional molecules can exist in right-handed and left-handed mirror-image forms (enantiomers), exactly like pairs of shoes. They have the property of “chirality”. When this happens with drug compounds, it’s generally the case that the two have different activities, because proteins in the body are chiral, too. Where that handedness comes from is a rather deep question. Separating enantiomers is generally done by using another chiral substance (making derivatives or salts of the parent compound or passing across a purification column loaded with some chiral solid phase].

There have been a number of proposals in this vein, although it’s a minefield of subtlety (and of irreproducible experiments). But there are some electromagnetic effects that are both theoretically feasible and experimentally real, and this new paper seems to be another one. The paper starts off, I should note, with a brief history on the intersection of chirality and magnetism, a topic that involved heavy hitters like Pasteur, Lord Kelvin, and Pierre Curie in its early days. During my own career, I well recall reports of chiral induction in magnetic fields that had to be retracted to much embarrassment, so it does take some bravery to venture into this area.

The authors, a multicenter team from Israel, the US, Germany, and Poland, are taking advantage of a phenomenon called chirality-induced spin selectivity (CISS). Simply put – and I’m not going to be able to put it at a much higher level – electron movement through molecules is affected by their chirality. And that means that charge distribution in two enantiomers has different spin polarization in each one. That led the group to wonder about the interaction of chiral molecules with perpendicularly-magnetized surfaces, which have been the subject of much research in thin-film “spintronic” applications. In theory, one enantiomer could be attracted to such a surface much more than the other, depending on the direction of the magnetic field.

And that’s just what happens. They picked a test helical polyalanine peptide and a gold-layered ferromagnet film (the gold is to protect it from oxidation, and the behavior of the exact peptide on gold layers had already been studied in other contexts). Attaching nanoparticles to the peptide (for visualization) and exposing these to the surface showed (by electron microscopy) a dramatic difference based on the direction of the perpendicular magnetic field. In one direction, the particles stick, and in the other they don’t. If the magnetization is in-plane (instead of perpendicular), there’s no difference, and there’s no difference if you’re applying an external magnetic field instead. It has to be a field associated with the thin layer, and it has to be in the right direction.

The group also prepared a 50/50 mix of D- and L-peptides, and this (as it should) shows no circular dichroism. But after multiple exposures to fresh magnetic surfaces, the solution was clearly enriched in one enantiomer, and began to show circular dichroism as expected, increasing with the number of exposures. They then set this up as a flow experiment, and the results were unmistakeable: flowing an an enantiomeric mixture of two peptides down an unmagnetized column gave the same racemic mixture out the other end. But when the surface was magnetized “perpendicular down”, they got a strong CD spectrum from the eluent, and when it was magnetized “perpendicular up”, they got the mirror-image CD spectrum: the other enantiomer. The D enantiomers interact with the down-magnetized surfaces and the L enantiomers with the up.

It’s not just peptides, either. A DNA oligomer was shown to bind to one magnetization and not the other, and the effect was reproduced with the single amino acid cysteine. In each case the kinetics are different for different sorts of molecules, different at various concentrations, and different between the enantiomers. The system thus has to be tuned for the best separation, but the effect is real across all of them. And that immediately suggests a whole new kind of chromatography:

The enantioselective interaction of chiral molecules with a magnetic substrate, presented in this article, provides a potentially generic chromatographic method for enantioseparation, which does not require a specific separating column. Because the observed effect depends on the electrical polarizability of the system (that is accompanied by spin polarization) and because this polarization depends on the global structure of the chiral molecule, the method described here may also allow the separation of chiral molecules from a mixture of molecules, either chiral or achiral. In addition, this technique could potentially be applied for separating chiral molecules based on their secondary structure and/or for separating two secondary structures of the same chiral molecule.

It would appear that a completely new analytical method has been invented, and I very much look forward to seeing what can be made out of it. We’re going to have to learn to think about chiral separations in a completely different way than we’re used to!