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.

阿尔茨海默氏病（AD）是一种复杂的多因素疾病，具有重要的健康和金融社会影响，因为没有有效抵消疾病的药物。 AD的特征是突触受损可塑性导致缺陷海马依赖性记忆，在很久以前就发现了这一记忆淀粉样斑块和神经元细胞死亡的积聚。该观察结果表明针对干预措施调节突触可塑性的生物学途径可能会提供减慢，逮捕和/或防止的方法神经退行性过程的进展。该提议的目的是确定一等小规模的小具有双重目标活性的分子，可增强突触可塑性。在初步研究中，我们发现两个不同的分子靶标，磷酸二酯酶5（PDE5）和组蛋白乙酰转移酶（HAT）在突触可塑性。我们开发了能够营救的小分子PDE5抑制剂和帽子激活剂小鼠海马切片中突触可塑性受损。在一项概念证明的研究中，我们证明了使用PDE5抑制剂和帽子激活剂的组合处理可产生突触的高6倍与仅使用两种化合物的治疗相比，可塑性。这些发现表明调整这些与单一目标疗法相比，AD涉及的两个靶标提供了更有效的治疗方法。在这个建议中，我们计划测试通过新合成的单分子调节PDE5和HAT活动的假设导致一种新颖的广告处理。多目标定向配体方法将用于达到PDE5 抑制剂/帽子激活剂药物分子。这种方法已成为治疗的有益策略复杂疾病并在组合疗法方面呈现出几个优势，包括增加治疗效率，降低药物相互作用和简化药物方案。具体来说，我们将测试我们的通过以下特定目的假设：1）设计和合成新的双目标分子库 HAT和PDE5活性，2）阐明我们新合成的药代动力学/药效学特性体外和体内的双目标分子，以及3）衍生的小鼠海马切片中的突触可塑性从我们新合成的双目标处理的一般修饰的淀粉样蛋白沉积的小鼠模型配体。这些目标将通过结合生成的医学化学方法来解决新的化学实体以及测试生物学活性的生化和电生理技术这些新的双重靶分子体外以及评估其体内效率。这些结果实验将为治疗基于AD的替代和新颖的治疗方法提供关键的见解巧妙地调节已知的两个分子靶标在该疾病的病理学中发挥重要作用。