Molecular chaperone slows prion disease

There are no treatments available for prion-based diseases, which often lead to dementia, muscle dysfunction, and early death. Some researchers are looking instead for ways to slow progression of the diseases. A team of researchers in Japan has created a molecular chaperone that, in mice, appears to slow the decline associated with prion-based diseases, including the well-known bovine spongiform encephalopathy (BSE). The chaperone, N,N′-([cyclohexylmethylene]di-4,1-phenylene)bis(2-[1-pyrrolidinyl]acetamide), was built from a less active compound using custom software developed in the lab of Kazuo Kuwata of Gifu University. To make the most active chaperone, the team modeled modifications to the less active compound, searching for the best affinity for prion proteins, and modeled the energetics of how those proteins would behave in the presence of the various candidates. The researchers gave mice with a prion disease weekly injections of the best candidate, which they have named MC. Those mice lived longer than diseased animals treated only with saline, and their brains showed less damage. The team also tested MC on macaques with BSE. Macaques that were treated with MC before symptoms began to appear showed no signs of disease progression—tremor, paralysis, slowed movement, and twitching—compared with macaques given MC after symptoms appeared or not treated with the compound. Kuwata says he is ready to test the compound in clinical trials and adds that the strategy used to design this drug could be applied to other neurodegenerative diseases (Nat. Biomed. Eng. 2019, DOI: 10.1038/s41551-019-0349-8).