Fellutamide Blocks Proteasome To Aid Neurons

The natural product fellutamide B aids brain cells by inhibiting the proteasome, the cell's garbage disposal for proteins, Yale researchers have found. The finding could aid the design of small-molecule therapies that promote the well-being of neurons. Craig M. Crews and coworkers show that fellutamide B, a small molecule isolated from a marine fungus, binds to caspase-, trypsin-, and chymotrypsin-like regions of the proteasome via a threonine residue. This binding inhibits enzyme-catalyzed protein hydrolysis in the proteasome, which, in turn, activates transcription of a polypeptide called nerve growth factor (NGF) (Chem. Biol., DOI: 10.1016/j.chembiol.2008.03.020). NGF, which protects existing neurons and can repair those damaged by injury or disease, has shown potential for treatment of neuronal injuries such as stroke, as well as Parkinson's and Alzheimer's diseases. However, when administered directly, NGF cannot cross the blood-brain barrier, greatly limiting its potential as a treatment for such diseases. Fellutamide B, in contrast, is small enough that it potentially could cross the blood-brain barrier and stimulate NGF synthesis within brain cells.