Department of Drug Discovery and Development, Auburn University, Auburn, AL 36879, USA.
Department of Pharmaceutical and Biomedical Sciences, Touro College of Pharmacy, New York, NY 10027, USA.
Cells. 2023 Apr 8;12(8):1116. doi: 10.3390/cells12081116.
The continuously increasing association of Alzheimer's disease (AD) with increased mortality rates indicates an unmet medical need and the critical need for establishing novel molecular targets for therapeutic potential. Agonists for peroxisomal proliferator activating receptors (PPAR) are known to regulate energy in the body and have shown positive effects against Alzheimer's disease. There are three members of this class (delta, gamma, and alpha), with PPAR-gamma being the most studied, as these pharmaceutical agonists offer promise for AD because they reduce amyloid beta and tau pathologies, display anti-inflammatory properties, and improve cognition. However, they display poor brain bioavailability and are associated with several adverse side effects on human health, thus limiting their clinical application. : We have developed a novel series of PPAR-delta and PPAR-gamma agonists in silico with AU9 as our lead compound that displays selective amino acid interactions focused upon avoiding the Tyr-473 epitope in the PPAR-gamma AF2 ligand binding domain. : This design helps to avoid the unwanted side effects of current PPAR-gamma agonists and improve behavioral deficits and synaptic plasticity while reducing amyloid-beta levels and inflammation in 3xTgAD animals. : Our innovative in silico design of PPAR-delta/gamma agonists may offer new perspectives for this class of agonists for AD.
阿尔茨海默病（AD）与死亡率不断增加之间的持续关联表明存在未满足的医疗需求，迫切需要为治疗潜力建立新的分子靶点。已知过氧化物酶体增殖物激活受体（PPAR）激动剂可调节体内能量，并且已显示出对阿尔茨海默病的积极作用。该类有三个成员（δ、γ和α），其中 PPAR-γ研究最多，因为这些药物激动剂有望用于 AD，因为它们可减少淀粉样β和tau 病理学，显示出抗炎特性，并改善认知。但是，它们在大脑中的生物利用度较差，并且与人类健康的几种不良副作用相关，从而限制了它们的临床应用。
我们已经在计算机上设计了一系列新型的 PPAR-δ和 PPAR-γ激动剂，以 AU9 作为我们的先导化合物，该化合物显示出选择性氨基酸相互作用，重点是避免 PPAR-γ AF2 配体结合域中 Tyr-473 表位。
这种设计有助于避免当前 PPAR-γ激动剂的不良副作用，并改善 3xTgAD 动物的行为缺陷和突触可塑性，同时降低淀粉样β水平和炎症。
我们对 PPAR-δ/γ激动剂的创新性计算机设计可能为这一类 AD 激动剂提供新的视角。
