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，对健康和金融社会具有重大影响影响，因为没有药物可以有效对抗 AD 的特点是突触受损。可塑性导致海马依赖性记忆缺陷，人们发现这种缺陷早在大脑形成之前就出现了。这一观察结果表明，针对淀粉样蛋白斑块的积累和神经细胞死亡。调节突触可塑性的生物途径可能提供一种减缓、阻止和/或预防突触可塑性的方法。该提案的目的是确定一流的小分子。在初步研究中，我们发现具有增强突触可塑性的双重靶点活性的分子。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) 在我们开发了能够挽救突触可塑性的小分子 PDE5 抑制剂和 HAT 激活剂。在一项概念验证研究中，我们证明了小鼠海马切片的突触可塑性受损。 PDE5 抑制剂和 HAT 激活剂联合治疗可将突触拯救率提高 6 倍与单独使用两种化合物的治疗相比，这些发现表明调节这些。 AD 中涉及的两个靶点提供了比单靶点治疗更有效的治疗方法。计划检验以下假设：通过新合成的单分子调节 PDE5 和 HAT 活性将多靶点定向配体方法将用于获得 PDE5。抑制剂/HAT 激活剂药物分子这种方法已成为治疗 HAT 的有益策略。复杂的疾病，并在联合治疗方面具有多种优势，包括增加具体来说，我们将测试我们的治疗效果、减少药物相互作用和简化药物治疗方案。通过以下具体目标提出假设：1）设计和合成新的双靶分子库 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双靶分子，3) 评估小鼠海马切片的突触可塑性来自用我们新合成的双靶点处理的淀粉样蛋白沉积转基因小鼠模型这些目标将通过结合药物化学方法来实现。新的化学实体以及用于测试生物活性的生化和电生理技术这些新的双靶分子在体外以及评估其体内功效的结果。实验将为治疗 AD 的替代和新颖的治疗方法提供重要见解巧妙地调节已知在该疾病的病因病理学中发挥重要作用的两个分子靶标。