Kaupang Åsmund, Hansen Trond Vidar
Section for Pharmaceutical Chemistry, Department of Pharmacy, University of Oslo, 0316 Oslo, Norway.
PPAR Res. 2020 Jul 1;2020:9657380. doi: 10.1155/2020/9657380. eCollection 2020.
The past decade of PPAR research has dramatically improved our understanding of the structural and mechanistic bases for the diverging physiological effects of different classes of PPAR ligands. The discoveries that lie at the heart of these developments have enabled the design of a new class of PPAR ligands, capable of isolating central therapeutic effects of PPAR modulation, while displaying markedly lower toxicities than previous generations of PPAR ligands. This review examines the emerging framework around the design of these ligands and seeks to unite its principles with the development of new classes of ligands for PPAR and PPAR. The focus is on the relationships between the binding modes of ligands, their influence on PPAR posttranslational modifications, and gene expression patterns. Specifically, we encourage the design and study of ligands that primarily bind to the pockets of PPAR and PPAR. In support of this development, we highlight already reported ligands that if studied in the context of this new framework may further our understanding of the gene programs regulated by PPAR and PPAR. Moreover, recently developed pharmacological tools that can be utilized in the search for ligands with new binding modes are also presented.
过去十年的过氧化物酶体增殖物激活受体（PPAR）研究极大地增进了我们对不同类别PPAR配体产生不同生理效应的结构和机制基础的理解。这些进展的核心发现使得能够设计出一类新型PPAR配体，这类配体能够分离出PPAR调节的主要治疗效果，同时显示出比前代PPAR配体显著更低的毒性。本综述考察了围绕这些配体设计的新兴框架，并试图将其原理与PPAR和PPAR新型配体的开发相结合。重点在于配体的结合模式、它们对PPAR翻译后修饰的影响以及基因表达模式之间的关系。具体而言，我们鼓励设计和研究主要结合PPAR和PPAR口袋的配体。为支持这一进展，我们强调了已经报道的配体，如果在这个新框架的背景下进行研究，可能会加深我们对由PPAR和PPAR调节的基因程序的理解。此外，还介绍了最近开发的可用于寻找具有新结合模式配体的药理学工具。
