Discovery of novel mitophagy activators for Alzheimer´s disease
Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegeneration. Failure to clear cellular damaged mitochondria is majorly caused by compromised mitophagy. Turning up mitophagy via pharmaceutical approaches could improve brain health, healthspan, and lifespan. We aim to use our in-house artificial intelligence plus wet lab validation platform to identify and characterize new drug candidates for activation of mitophagy with a positive impact on Alzheimer's disease.
Alzheimer’s disease (AD) affects over 35 million people worldwide and causes formidable economic challenges. Since 2003, over 250 drug candidates, predominantly targeting two pathological proteins, amyloid-β (Aβ) and pathological Tau, have been tested in clinical trials for AD, but most of them have failed. There is a need to pursue new mechanistic studies in order to better understand the underlying causes of AD, and to discover new drug targets. Mitochondria operate as cellular “powerhouses” and play a pivotal role in neuroplasticity and memory, thus dysfunction in mitochondria can impair neuronal function and trigger neurodegeneration. The homeostatic maintenance of functional mitochondria is crucial for neuronal health and survival. Mitochondria are constantly exposed to stress and damage; to cope, dysfunctional mitochondria must be specifically and efficiently eliminated via a cellular self-clearance system, “mitophagy”. Mitophagy is impaired in the elderly, leading to the accumulation of damaged mitochondria. The impaired energy production brought about by these dysfunctional mitochondria manifests in the senescence, inflammation, and neuronal loss seen in the elderly, and in AD patients. Large-scale omics and functional studies using post-mortem brain tissues and iPSCs from AD identified impaired mitochondrial function and impairment of mitochondria-related pathways as major changes in AD. My group was one of the very first research teams to propose defective mitophagy as a key driver in AD initiation and progression and to demonstrate its causative role; we have demonstrated the effectiveness of mitophagy induction in inhibiting memory loss in multiple AD animal models (Trends Neurosci 2017; Nature Neurosci 2019; Cell Metabolism 2019; Nature Biomedical Engineering 2022). Previous work has highlighted how impaired mitophagy coincides with the behavioural and pathological development and progression of AD. Genetic and pharmacological promotion of mitophagy rescued cognitive decline in AD models, and inhibited the phosphorylation of Tau (p-Tau) in both human cell lines and 3xTgAD mice. However, robust neuronal mitophagy inducers with clinical potential, that is to induce mitophagy but without causing mitochondrial damage at the same dose, is sparse. Very recently, we have established an artificial intelligence (named Fang-AI) plus wet lab validation platform, enabled us successful identification of two lead compunds as drug candidates for AD. This proposal aims to use the ‘Fang-AI’ plus our wet lab platform (C. elegans, mice and iPSCs) to swiftly identify new drug candidates for AD. As defective mitophagy is likely a shared cause of different neurodegenerative diseases (such as Parkinson’s disease/PD, Huntington’s disease/HTT, and Amyotrophic Lateral Sclerosis/ALS), turning up mitophagy via pharmaceutically approaches could be a druggable target for broad neurodegenerative diseases.
WP1: To use our established Fang-AI + wet lab validation platform to screen new mitophagy inducers • To use our established Fang-AI + wet lab validation platform to screen new mitophagy inducers from the Finnish Institute of Molecular Medicine (FIMM), consisting 140,000 compounds (U. Helsinki, with access). We will perform AI screening and wet lab verification as detailed in our recent publication in Nature Biomedical Engineering 2022. We have already identified 26 molecules from the FIMM library (AI score ≥0.8) such as FIMM136359, 104757, 106153, etc. WP2: AI-based structure modifications for drug candidates EFF-AA and EFF-BA, and wet lab validation experiments Unpublished data from the Fang group have identified two structurally similar natural compunds EFF-AA and EFF-BA. They are robust mitophagy inducers with high translational potential as EFF-AA and EFF-BA induce mitophagy at 10% dose as used for other compunds (e.g, compunds K and R8), and without detectible toxicity in the bioactive doses in cells and C. elegans. For the purpose of further optimization and patent, we aim • To use machine learning to provide suggestions on structure modifications on current known mitophagy inducers (EFF-AA, EFF-BA), aiming to increase ‘solubility’, ‘activity’, ‘bioavailability’ and to reduce ‘toxicity’; • To work with chemists and pharmacists to select from the ‘AI-suggested list’, and to synthesize new compunds (the first two steps will be done via paid service to the experienced medchem CRO companies, such as Spirochem or Symeres); and • To use wet lab techniques (majorly cell culture and C. elegans) to validate bioactivity and anti-AD function of the new compunds. • Patent applications (note, background IP will apply) Commercial Viability - EFF-AA could be considered for patenting or direct commercial use (e.g. diet supplement) - Target deconvolution of EFF-AA and development of new chemical compounds with distinct target profiles
Toxicity assays for FIMM hitsRequired Funding$26,815
Assess toxicity of potential mitophagy inducers identified from FIMM library in cell based assays (quantitative criteria tbd.)
Toxicity and efficacy of EFF-AA/EFF-BARequired Funding$81,565
Assess toxicity and EC50 values of mitophagy inducers EFF-AA/EFF-BA in cell based assays (quantitative criteria tbd.)
Mitophagy assays of FIMM hitsRequired Funding$63,500
Positive outcome of mitophagy induction assays of FIMM hits (quantitative criteria tbd.)
Chemical synthesis of EFF-AA/EFF-BA analoguesRequired Funding$63,500
Succesful synthesis of selected EFF-AA/EFF-BA analogues (AI platform, med chem assessment) via paid service by an experienced CRO (Spirochem or Symeres)