Scientists say they have are uncovered a method to tone down an overactive gene involved in colon cancer and block a key protein involved in asthma attacks. Those targets long had ranked among hundreds of thousands that many scientists considered to be “undruggable,” meaning that efforts to reach them with conventional medicines were doomed to fail.
“These substances represent an entirely new class of potential drugs,” study leader and chemical biologist Gregory Verdine, Ph.D. of Harvard University said recently at a meeting of the American Chemical Society
The new substances are “stapled peptides,” – protein fragments outfitted with chemical braces or “staples.” The stapling gives peptides a stronger, more stable architecture and the ability to work in ways useful in fighting disease.
“Our new stapled peptides can overcome the shortcomings of drugs of the past and target proteins in the body that were once thought to be undruggable,” Verdine said.
In colon cancer, stapled peptides inhibit activity of a protein called beta-catenin that, when present in a hyperactive form, causes cells to grow in an aggressive and uncontrolled way. That protein normally helps keep certain cells, including those lining the colon, in good health. But the abnormal protein has been directly linked with an increased risk of colon cancer and other types of cancer, including those of the skin, brain, and ovaries.
When added to human colon cancer cells growing in laboratory cultures, the stapled peptides reduced the activity of beta-catenin by 50 percent. In patients, that level of reduction could be sufficient to have a beneficial impact on the disease, Verdine suggested.
Verdine and colleagues developed stapled cytokines, which he says shows promise for fighting asthma. Cytokines are hormone-like proteins secreted by cells of the immune system and other body systems that help aid signal exchanges between cells. The stapled cytokines moderate the activity of a cytokine called interleukin-13, which asthma patients produce in abnormally large amounts, which contribute to asthma attacks.
Current asthma drugs, he noted, tend to treat the underlying symptoms of asthma, particularly inflammation. By contrast, stapled cytokines could treat the underlying causes of the disease. The team is collaborating with a pharmaceutical firm on efforts to further develop the stapled peptides.
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