P1‐093: Novel Partial Mitochondrial Complex I Inhibitors as Disease‐modifying Therapeutics for Treatment of Alzheimer's Disease
Year: 2019
Type: article
Abstract: Alzheimer's Disease (AD) has no effective treatments, and recent clinical trials focused on prevention of amyloid beta (Ab) production have consistently failed. Alternative approaches are urgently needed. We recently demonstrated that modulation of mitochondrial function with a small molecule tricyclic pyrone compound CP2 prevents the development of cognitive and behavior phenotypes in transgenic animal models of familial AD. Low-mass molecular dynamics simulation revealed that CP2 competes with the flavin mononucleotide (FMN) for binding to the redox center of mitochondrial complex I (MCI) partially reducing its activity. We conducted extensive structure-activity relationship (SAR) studies to characterize four novel classes of compounds partial complex I inhibitors synthesized using rational design including a new lead compound NSMC00594. Target engagement, selectivity and specificity of new compounds were established using multiple in vitro and cellular assays including primary mouse neurons. We demonstrated that the lead NSMC00594 directly binds and competes with the FMN for binding to complex I using pulldown, proteomics, competitive binding assay and surface plasmon resonance (SPR) approaches. In primary neurons, MCI inhibitors activate AMPK-a, Sirtuins 1and 3, and upregulate PGC-1a leading to enhanced mitochondrial biogenesis. In vivo, chronic administration of NSMC00594 did not affect the development and had no detectable toxicity at therapeutic doses (25 and 50 mg/kg/day). NSMC00594 has excellent oral bioavailability and blood–brain-barrier penetration. NSMC00594 was remarkably clean in 250 kinase panel. Finally, in pre-symptomatic APP/PS1 mice, treatment with NSMC00594 resulted in cognitive protection and improved long-term potentiation after 6 months of chronic oral administration (25 mg/kg/day). Furthermore, APP/PS1 mice treated with NSMC00458 showed a significant increase in metabolic rates and glucose brain uptake and utilization detected with translational FDG-PET imaging as well as an enhancement of ATP production in the brain measured in vivo with P NMR. Mechanistic studies demonstrate that MCI inhibitors induce protective stress response increasing mitochondrial biogenesis and turnover, augmenting cellular energetics and the protection against oxidative stress. Our studies demonstrate that modulation of MCI activity using novel FMN MCI inhibitors improves bioenergetics in the brain and averts cognitive decline in Alzheimer's Disease representing novel therapeutic approach.
Source: Alzheimer s & Dementia
Institution: Mayo Clinic
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4249003377