Proline method adds dichloromethyl handles to drugs
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- Prof. Dmitry Tsvelikhovsky led a Hebrew University team that published a proline-based method in Nature Communications for attaching dichloromethyl groups to complex drug molecules, replacing aggressive heavy-metal or radiation-heavy techniques used previously.
- Proline functions as a temporary "molecular machine" that binds to the target molecule and aligns it into a highly specific shape, shifting the molecule's internal electronics to incorporate the new chemical handle.
- The reaction features a built-in "stereochemically gated" self-correction system that allows only the perfectly configured three-dimensional arrangement to proceed, shunting mismatched arrangements back to their original components during cleanup.
- The dichloromethyl group acts as an anchor point prized by pharmaceutical chemists for tweaking molecular structures to improve safety or efficacy, and was previously considered a chemical dead end for delicate molecules.
- The Hebrew University team demonstrated the method directly on molecular frameworks used to build next-generation antibiotics, natural products, and serotonin-receptor-targeting neuroactive compounds.
- The study was authored by Elihay Kuniavsky, Dvora R. Levy, and Tsvelikhovsky at the Institute for Drug Research and published in Nature Communications (2026) with DOI 10.1038/s41467-026-71815-z.
Why it matters: Medicinal chemists gain a programmable platform for building drug compounds — including antibiotics and serotonin-receptor neuroactive drugs — that were previously considered impossible to synthesize cleanly. The built-in stereochemical gatekeeping eliminates a major source of unwanted byproducts, potentially shortening development timelines for complex therapies.
