Markham Lauren E, Koelblen Thomas, Chobanian Harry R, Follis Ariele Viacava, Burris Thomas P, Micalizio Glenn C
Department of Chemistry, Dartmouth College, 6128 Burke Laboratory, Hanover, New Hampshire 03755, United States.
University of Florida Genetics Institute, P.O. Box 103610, 2033 Mowry Road, Gainesville, Florida 32610, United States.
ACS Cent Sci. 2024 Feb 12;10(2):477-486. doi: 10.1021/acscentsci.3c01155. eCollection 2024 Feb 28.
Fatty acids play important signaling roles in biology, albeit typically lacking potency or selectivity, due to their substantial conformational flexibility. While being recognized as having properties of potentially great value as therapeutics, it is often the case that the functionally relevant conformation of the natural fatty acid is not known, thereby complicating efforts to develop natural-product-inspired ligands that have similar functional properties along with enhanced potency and selectivity profiles. In other words, without structural information associated with a particular functional relationship and the hopelessly unbiased conformational preferences of the endogenous ligand, one is molecularly ill-informed regarding the precise ligand-receptor interactions that play a role in driving the biological activity of interest. To address this problem, a molecular strategy to query the relevance of distinct subpopulations of fatty acid conformers has been established through "conformational profiling", a process whereby a unique collection of chiral and conformationally constrained fatty acids is employed to deconvolute beneficial structural features that impart natural-product-inspired function. Using oleic acid as an example because it is known to engage a variety of receptors, including GPR40, GPR120, and TLX, a 24-membered collection of mimetics was designed and synthesized. It was then demonstrated that this collection contained members that have enhanced potency and selectivity profiles, with some being clearly biased for engagement of the GPCRs GPR40 and GPR120 while others were identified as potent and selective modulators of the nuclear receptor TLX. A chemical synthesis strategy that exploited the power of modern technology for stereoselective synthesis was critical to achieving success, establishing a common sequence of bond-forming reactions to access a disparate collection of chiral mimetics, whose conformational preferences are impacted by the nature of stereodefined moieties differentially positioned about the C skeleton of the parent fatty acid. Overall, this study establishes a foundation to fuel future programs aimed at developing natural-product-inspired fatty acid mimetics as valuable tools in chemical biology and potential therapeutic leads.
脂肪酸在生物学中发挥着重要的信号传导作用，尽管由于其显著的构象灵活性，它们通常缺乏效力或选择性。虽然人们认识到脂肪酸具有作为治疗剂的潜在巨大价值的特性，但通常情况下，天然脂肪酸的功能相关构象是未知的，这使得开发具有类似功能特性以及增强的效力和选择性的天然产物启发的配体变得复杂。换句话说，没有与特定功能关系相关的结构信息以及内源性配体毫无偏向的构象偏好，就无法从分子层面准确了解在驱动感兴趣的生物活性中起作用的精确配体 - 受体相互作用。为了解决这个问题，通过“构象剖析”建立了一种分子策略，用于探究脂肪酸构象异构体不同亚群的相关性，在这个过程中，使用了一组独特的手性和构象受限脂肪酸来解析赋予天然产物启发功能的有益结构特征。以油酸为例，因为已知它能与多种受体相互作用，包括GPR40、GPR120和TLX，设计并合成了一个包含24个成员的模拟物集合。然后证明这个集合中的成员具有增强的效力和选择性，其中一些明显偏向于与GPCRs GPR40和GPR120结合，而其他一些被鉴定为核受体TLX的有效和选择性调节剂。利用现代技术进行立体选择性合成的化学合成策略对于取得成功至关重要，建立了一个共同的键形成反应序列来获得不同的手性模拟物集合，其构象偏好受到围绕母体脂肪酸C骨架不同位置的立体定义部分性质的影响。总体而言，这项研究为推动未来旨在开发天然产物启发的脂肪酸模拟物作为化学生物学中有价值的工具和潜在治疗先导的项目奠定了基础。
