Benign by Design The search for biodegradable drugs by Anthony King
W
hen Israeli scientists tested vegetables for the epilepsy drug carbamazepine, they detected it in cucumbers, carrots, lettuce, and peppers. More surprisingly, people who ate the vegetables had a surge of the epilepsy drug in their urine—albeit in the nanograms. “So much reclaimed wastewater is being used for irrigation that we wanted to see whether some residues can pass from water to the soil to the crop to people,” explains study author Benny Chefetz of the Hebrew University of Jerusalem, Israel. The quantities were minuscule (one thousand-millionth of a gram) and there was no risk of death or instant illness from the drug residues, so the vegetables stayed on the market. It’s an oft-told tale. Most drugs we take, we excrete. The remnants flow on to treatment plants, and some drugs flow out in treated water—more, it turns out, than we previously thought. As chemistry instruments advanced over the past decade, scientists expanded the list of leftovers detected in rivers, streams, and wildlife. The US Geological Survey reported in 2016 that it had detected at least one out of 108 pharmaceuticals it tested for in small streams in the eastern US. The average number detected was six. Our prescription habit, it seems, has blanketed the Anthropocene with a variable drug cocktail. One solution is to intensify the cleaning process. Switzerland has spent huge sums upgrading its treatment facilities to remove micro-pollutants. Yet many countries cannot afford this strategy. Eighty percent of active pharmaceutical ingredients are made in China and India, where water treatment standards are generally poor. What’s more, some argue, treatment is not just expensive but potentially harmful. Professor Klaus Kümmerer at Leuphana University in Lüneburg, Germany, is of this view. He says high-tech treatments can convert pharmaceuticals into biologically active molecules that we know even less about. Kümmerer began his academic career looking at pollutants in the environment. What he saw forced him to switch his attention to the other end of the pipeline—the creation of new drugs. He advocates “benign by design,” a concept he began promoting more than ten years ago. Under this new creed, drug companies should look at biodegradability as desirable during
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Chemistry International
July-September 2022
drug development. Drugs would be designed to break down naturally. When he first talked about this concept at a pharma conference in London in 2006, his audience sat stunned. Drug developers were horrified: it is already difficult to come up with a new drug, and now you want it to biodegrade. That’s crazy talk, they said. Drug developers and regulators seek stability, not instability. But Kümmerer persisted. Tests he carried out indicated that between 15 and 20 percent of drugs on the market were already—accidentally—biodegradable. It is normal to have a lead drug structure and to alter parts of the molecule to improve it, to optimize its biological effect, or to reduce side effects. “Designing for biodegradable drugs would just add another criterion when selecting from promising candidates,” says Kümmerer. There are chemistry basics that guide whether a compound will biodegrade. Many molecules in nature are linear carbon chains, made up of carbon-to-carbon bonds; natural enzymes in bacteria chew these bonds apart. However, highly branched carbon chains with three carbons stuck together resist natural enzymes and persist. Knowing and tweaking the chemistry of drug molecules could ensure they break down in the environment, not in storage.
