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Development of First-in-Class PDE5/HAT Directed LigandsModulating Molecular Pathways involved in Synaptic Plasticity

开发一流的 PDE5/HAT 定向配体调节参与突触可塑性的分子途径

基本信息

批准号：
10654103
负责人：
Jole Fiorito
金额：
$ 43.86万
依托单位：
NEW YORK INST OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654103
关键词：
AD transgenic mice Acetylation Address Aducanumab Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease therapy Amyloid deposition Binding Proteins Biochemical Biological Biological Assay Biological Availability Biological Testing Brain Chemical Structure Combined Modality Therapy Communication Complex Cyclic AMP Cyclic GMP Development Disease Disease Progression Drug Design Drug Interactions Drug Kinetics Drug toxicity Electrophysiology (science)Elements Enzyme-Linked Immunosorbent Assay Enzymes Event FDA approved Future Galantamine Gene Expression Genes Goals Health Hippocampus Histone Acetylation Histones Hybrids Impairment In Vitro Individual Intervention Knowledge Laboratories Learning Libraries Ligands Long-Term Potentiation Lysine Measures Memantine Memory Modification Molecular Molecular Target Mus Nerve Degeneration Neurons Nitric Oxide Pathway Pathologic Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Phosphorylation Plasma Play Process Property Proteins Regimen Research Research Proposals Role Second Messenger Systems Senile Plaques Slice Societies Solubility Symptoms Synapses Synaptic Transmission Synaptic plasticity Techniques Testing Therapeutic Toxic effect Translating Treatment Efficacy Wild Type Mouse behavioral study blood-brain barrier crossing design donepezil effective intervention effective therapy enzyme activity experimental study histone acetyltransferase improved in vivo inhibitor innovation insight intraperitoneal lead candidate lipophilicity liquid chromatography mass spectrometry mouse model neuron loss new chemical entity novel novel therapeutic intervention novel therapeutics pharmacologic phosphodiesterase V phosphoric diester hydrolase preclinical study prevent rivastigmine single molecule small molecule success targeted treatment therapeutic candidate treatment strategy

项目摘要

Alzheimer’s disease (AD) is a complex, multifactorial disease with a significant health and financial societal impact as there are no drugs that effectively counteract the disease. AD is characterized by impaired synaptic plasticity leading to defective hippocampal-dependent memory, which has been found to appear long before the buildup of amyloid plaques and neuronal cell death. This observation suggests that interventions targeting biological pathways that regulate synaptic plasticity may provide a way to slow down, arrest, and/or prevent the progression of neurodegenerative processes. The objective of this proposal is to identify first-in-class small molecules with dual target activity that enhance synaptic plasticity. In preliminary studies, we discovered that two distinct molecular targets, phosphodiesterase 5 (PDE5) and histone acetyltransferase (HAT) are crucial in synaptic plasticity. We developed small molecule PDE5 inhibitors and HAT activators that are able to rescue impaired synaptic plasticity in mouse hippocampal slices. In a proof-of-concept study, we demonstrated that a combination treatment with a PDE5 inhibitor and a HAT activator produces a 6-fold higher rescue of synaptic plasticity compared to treatment with the two compounds alone. These findings indicate that modulating these two targets involved in AD provides a more effective treatment than a single-target therapy. In this proposal, we plan to test the hypothesis that modulating PDE5 and HAT activity via a newly synthesized single molecule will result in a novel AD treatment. The multi-target directed ligand approach will be used to attain a PDE5 inhibitor/HAT activator drug molecule. This approach has emerged as a beneficial strategy for the treatment of complex diseases and presents several advantages with respect to combination therapy, including increased therapeutic efficacy, reduced drug-drug interactions, and simplified drug regimen. Specifically, we will test our hypothesis via the following specific aims: 1) design and synthesis of a library of new dual-target molecules with HAT and PDE5 activity, 2) elucidate the pharmacokinetic/pharmacodynamic properties of our newly synthesized dual-target molecules in vitro and in vivo, and 3) assess synaptic plasticity in mouse hippocampal slices derived from a genetically modified mouse model of amyloid deposition treated with our newly synthesized dual-target ligands. These aims will be addressed through a combination of medicinal chemistry approaches for generating new chemical entities, and biochemical and electrophysiological techniques for testing the biological activity of these new dual target molecules in vitro as well as assessing their in vivo efficacy. Results from these experiments will provide crucial insights into an alternative and novel therapeutic approach for treating AD based on cleverly modulating two molecular targets known to play a significant role in the etiopathology of this disease.

阿尔茨海默病（AD）是一种复杂的多因素疾病，具有重大的健康和经济社会意义