This technology includes a group of eight AMPK activating compounds to be further developed for the treatment of Niemann Pick Type C (NPC) disease. Through the recent molecular biology and pharmacological experiments, we have identified the cyclodextrin which directly binds to beta-subunits of AMP-activated protein kinase (AMP), resulting in subsequently activations of AMPK and AMPK linked autophagy, and restoration of autophagy function that is impaired in the NPC cells. Based on this knowledge, we performed computer-modeling research of compounds binding to AMPK beta subunits that led to identification of a group of AMPK activating compounds. We further found that this group of eight compounds (AMPK modulators) also effectively reduced lysosomal cholesterol accumulation in NPC cells. Therefore, this group of AMPK modulators can be further developed for treatment of NPC.
The small molecule AMPK modulators can be optimized for better blood-brain-barrier penetration, and the allosteric modulation of AMPK function by these compounds is more tolerable as a treatment.