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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（Alzheimer's disease，AD）是一种复杂的多因素疾病，对健康和社会经济造成重大影响影响，因为没有有效对抗这种疾病的药物。AD的特征是突触受损，可塑性导致有缺陷的大脑依赖性记忆，这已经被发现出现很久之前，淀粉样斑块的形成和神经细胞的死亡。这一观察结果表明，针对调节突触可塑性的生物学途径可以提供一种减缓、阻止和/或防止突触可塑性的方法。神经退行性过程的进展。本提案的目的是确定一流的小型具有双重靶点活性的分子，增强突触可塑性。在初步研究中，我们发现，磷酸二酯酶5（PDE 5）和组蛋白乙酰转移酶（HAT）是两个不同的分子靶点，突触可塑性我们开发了小分子PDE 5抑制剂和HAT激活剂，能够挽救小鼠海马脑片突触可塑性受损。在一项概念验证研究中，我们证明， PDE 5抑制剂和HAT激活剂的联合治疗产生了6倍更高的突触恢复，与单独使用两种化合物的处理相比，这些发现表明，调节这些涉及AD的两个靶点提供了比单靶点疗法更有效的治疗。在本提案中，我们计划测试通过新合成的单分子调节PDE 5和HAT活性的假设，导致新的AD治疗。多靶点定向配体方法将用于获得PDE 5 抑制剂/HAT激活剂药物分子。这种方法已成为治疗以下疾病的有益策略：对于复杂的疾病，并且相对于组合疗法呈现出几个优点，包括增加治疗功效、减少的药物-药物相互作用和简化的药物方案。具体来说，我们将测试我们的 1）设计和合成新的双靶分子库， HAT和PDE 5活性，2）阐明我们新合成的药物动力学/药效学特性体外和体内双靶分子，以及3）评估小鼠海马切片中的突触可塑性从我们新合成的双靶点治疗的淀粉样蛋白沉积的转基因小鼠模型中，配体。这些目标将通过药物化学方法的组合来解决，新的化学实体，以及用于测试生物活性的生物化学和电生理技术，这些新的双靶分子在体外以及评估其在体内的功效。从这些实验将为治疗AD的替代和新的治疗方法提供重要的见解，巧妙地调节两个分子靶点，这两个分子靶点在这种疾病的发病机制中起着重要作用。