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.
Project Team
Institutions
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Funding Opportunity
Background
Alzheimer’s disease (AD) affects over 35 million people worldwide and causes formidable economic challenges. 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. 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. 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. Genetic and pharmacological promotion of mitophagy rescued cognitive decline in AD models, and inhibited the phosphorylation of Tau in both human cell lines and mice. However, robust neuronal mitophagy inducers with clinical potential, that is to induce mitophagy but without causing mitochondrial damage at the same dose, are sparse. Very recently, we have established an artificial intelligence (named Fang-AI) plus wet lab validation platform, enabling us to successfully identify two lead compounds as drug candidates for AD. This proposal aims to use the ‘Fang-AI’ plus our wet lab platform (C. elegans, mice, and induced pluripotent stem cells (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, Huntington’s disease, and Amyotrophic Lateral Sclerosis/ALS), turning up mitophagy via pharmaceutical approaches could be a druggable target for broad neurodegenerative diseases.
Project Details
Phase 1: To use our established Fang-AI and wet lab validation platform to screen new mitophagy inducers from the Finnish Institute of Molecular Medicine (FIMM), consisting of 140,000 compounds. 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. Phase 2: Unpublished data from the Fang group have identified two structurally similar natural compounds EFF-AA and EFF-BA. They are robust mitophagy inducers with high translational potential as EFF-AA and EFF-BA induces mitophagy at a 10% dose as used for other compounds and without detectable toxicity in the bioactive doses in cells and C. elegans. AI-based structure modifications for drug candidates EFF-AA and EFF-BA, and wet lab validation experiments 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, aiming to increase solubility, activity, and bioavailability to reduce toxicity. • To work with chemists and pharmacists to select from the ‘AI-suggested list’, and to synthesize new compounds (the first two steps will be done via paid service to the experienced medicinal chemistry CRO companies, such as Spirochem or Symeres) • To use wet lab techniques (cell culture and C. elegans) to validate the bioactivity and anti-AD function of the new compounds. • 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
Project Timeline
Toxicity assays for FIMM hits
Required Funding$26,815
Statusplanned
Duration3 MonthsAssess toxicity of potential mitophagy inducers identified from FIMM library in cell based assays
Toxicity and efficacy of EFF-AA/EFF-BA
Required Funding$81,565
Statusplanned
Duration3 MonthsAssess toxicity and EC50 (half-maximal effective concentration) values of mitophagy inducers EFF-AA/EFF-BA in cell-based assays.
Mitophagy assays of FIMM hits
Required Funding$63,500
Statusplanned
Duration7 MonthsPositive outcome of mitophagy induction assays of FIMM hits
Chemical synthesis of EFF-AA/EFF-BA analogues
Required Funding$63,500
Statusplanned
Duration6 MonthsSuccesful synthesis of selected EFF-AA/EFF-BA analogues (AI platform, med chem assessment) via paid service by an experienced CRO (Spirochem or Symeres)