Terahertz light could enhance QC of chiral drugs

Researchers from the University of Michigan (U-M), US, have demonstrated that terahertz light can probe both the structures of molecular crystals and their chirality and therefore could be used to confirm the compositions and structures of therapeutics.

The technique could also help diagnose harmful accumulations of chiral molecules in the body, including bladder stones, insulin fibrils and amyloid aggregations such as the plaques that appear in Alzheimer’s disease.

Biology often favours right- or left-handed molecules, with the body using only one version. This ‘handedness’ is known as chirality and the direction of twist is noted by an L or D, representing clockwise or counterclockwise. Molecules with the wrong chirality can be nuisance fillers or cause unpleasant, if not serious, side effects.

However, ensuring the quality of substances that are chiral can be a challenge. Wonjin Choi, a research fellow in chemical engineering at U-M and first author of the paper in Nature Photonics, explained that the commonly used methods are very sensitive to impurities, but also expensive.

To combat this, an international team – including researchers at the Federal University of São Carlos in Brazil; the Brazilian Biorenewables National Laboratory; the University of Notre Dame in France; and Michigan State University – developed a new method. This technique, outlined in the Nature Photonics study, uses terahertz radiation to quickly identify incorrect chiral molecules and chemical structures within packaged drugs. Terahertz radiation is a portion of the infrared part of the light spectrum.

“Biomolecules support twisting, long-range vibrations also known as chiral phonons. These vibrations are very sensitive to the structure of molecules and their nanoscale assemblies, creating the fingerprint of a particular chiral structure,” explained Nicholas Kotov, the Irving Langmuir Distinguished University Professor of Chemical Sciences and Engineering at U-M and co-corresponding author.

This graph shows the terahertz circular dichroism spectra of five different brands of L-carnosine. While three samples show the same pattern of peaks, the measurement suggests possible differences from the remaining two samples [Credit: Wonjin Choi, Kotov Lab].

The team was able to measure these phonons in the spectra of twisted terahertz light that passed through tested materials. One of these, L-carnosine, is currently used as a nutritional supplement.

“If the twist of the molecule is wrong, if the twist in the way the molecules pack together is not right, or if different materials were mixed in, all of that could be inferred from the spectra,” Kotov added.

John Kruger, professor of veterinary medicine at Michigan State University and co-author of the paper, provided bladder stones from dogs and the team discovered their chiral signature. They hope that the findings could help enable rapid diagnostics for pets and perhaps later humans.

They also studied insulin as it grew into nanofibers that make it inactive. If the terahertz light technology can be adapted for home healthcare, it could verify the quality of insulin.

Moreover, the team explored how light can influence structures, rather than just measure them. Calculations carried out by André Farias de Moura, professor of chemistry at the Federal University of São Carlos and co-corresponding author, show that multiple biomolecules vigorously twist and vibrate when terahertz light generates chiral phonons.

“We foresee new roads ahead, for instance using terahertz waves with tailored polarisation to manipulate large molecular assemblies. It might replace microwaves in many synthesis applications in which the handedness of the molecules matters,” noted de Moura.

Based on de Moura’s calculations, Kotov and Choi believe that the twisting vibrations of chiral phonons caused by terahertz light may make disease-causing nanofibers more vulnerable to medical interventions. Future work will explore whether that interaction can be used to break them up.

This work was supported by the US Department of Defense, Office of Naval Research, Defense Advanced Research Projects Agency and National Science Foundation; Brazilian funding agencies CAPES and FAPESP; Japanese Society for the Promotion of Science and Yoshida Foundation; and U-M.