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Another step in the long road to hearing restoration

Memphis, Tennessee, December 1, 2015

St. Jude researchers discuss paper topics around a computer monitor

St. Jude researchers (From left) Anang Shelat, Ph.D., assistant member of the Chemical Biology and Therapeutics Department, Jian Zuo, Ph.D., member of the Developmental Neurobiology Department, Richard Kriwacki, Ph.D., member of the Structural Biology Department, and Luigi Iconaru, Ph.D., from the Developmental Neurobiology Department, discuss research topics. 

When it comes to reversing hearing loss, humans can learn from chickens. Both depend on sensory hair cells in the inner ear for proper hearing. But chickens and some other animals can grow replacement hair cells while humans cannot. In humans, hair cells lost to age, disease or damage, including as a side effect of cancer treatment, are a leading cause of hearing loss.

St. Jude Children’s Research Hospital scientists have identified small, drug-like molecules that help to lay the groundwork for growing new hair cells. The findings also raise hopes that drugs against a wide range of diseases, including cancer, may be on the horizon.

The research focused on a protein named p27. Like about one-third of human proteins, p27 does not spontaneously fold into a stable, specific 3-D shape. Most drugs are small molecules that work by binding proteins based on that 3-D shape. Efforts to develop drugs that target disordered proteins have so far failed.

Using powerful technologies and a specially assembled library of small molecules, researchers identified 36 small molecules that formed bonds with overlapping segments of p27. One of the molecules isolated the disordered protein and blocked p27 from performing its normal function. In the lab, blocking p27 is a required step in re-growing hair cells.

“While small-molecule compounds are a long way from the clinic, these results are another small step on the long road to a drug to combat hearing loss,” said Jian Zuo, PhD, of St. Jude Developmental Neurobiology. He and Richard Kriwacki, PhD, of St. Jude Structural Biology, led the research, which was published in the journal Scientific Reports.

Read the news release

Full Citation:
Iconaru LI, Ban D, Bharatham K, Ramanathan A, Zhang W, Shelat AA, Zuo J, Kriwacki RW. Discovery of Small Molecules that Inhibit the Disordered Protein, p27(Kip1). Sci Rep 5:15686, 2015. doi: 10.1038/srep15686.

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