Velander Paul, Wu Ling, Henderson Frances, Zhang Shijun, Bevan David R, Xu Bin
Department of Biochemistry, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA.
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
Biochem Pharmacol. 2017 Sep 1;139:40-55. doi: 10.1016/j.bcp.2017.04.004. Epub 2017 Apr 6.
Many chronic human diseases, including multiple neurodegenerative diseases, are associated with deleterious protein aggregates, also called protein amyloids. One common therapeutic strategy is to develop protein aggregation inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. These plant- or microorganism-extracted compounds have shown significant therapeutic potential from in vitro studies as well as in vivo animal tests. Despite the technical challenges of intrinsic disordered or partially unfolded amyloid proteins that are less amenable to characterizations by structural biology, a significant amount of research has been performed, yielding biochemical and pharmacological insights into how inhibitors function. This review aims to summarize recent progress in natural product-based amyloid inhibitors and to analyze their mechanisms of inhibition in vitro. Major classes of natural product inhibitors and how they were identified are described. Our analyses comprehensively address the molecular interactions between the inhibitors and relevant amyloidogenic proteins. These interactions are delineated at molecular and atomic levels, which include covalent, non-covalent, and metal-mediated mechanisms. In vivo animal studies and clinical trials have been summarized as an extension. To enhance natural product bioavailability in vivo, emerging work using nanocarriers for delivery has also been described. Finally, issues and challenges as well as future development of such inhibitors are envisioned.
许多慢性人类疾病，包括多种神经退行性疾病，都与有害的蛋白质聚集体有关，这种聚集体也被称为蛋白质淀粉样蛋白。一种常见的治疗策略是开发能够减缓、预防或重塑有毒淀粉样蛋白的蛋白质聚集抑制剂。天然产物是淀粉样蛋白抑制剂的一大类，近年来已经鉴定并表征了几十种基于天然产物的淀粉样蛋白抑制剂。这些从植物或微生物中提取的化合物在体外研究以及体内动物试验中都显示出了显著的治疗潜力。尽管内在无序或部分展开的淀粉样蛋白存在技术挑战，使其较难通过结构生物学进行表征，但已经开展了大量研究，从而在抑制剂的作用机制方面获得了生物化学和药理学见解。本综述旨在总结基于天然产物的淀粉样蛋白抑制剂的最新进展，并分析它们在体外的抑制机制。描述了天然产物抑制剂的主要类别及其鉴定方法。我们的分析全面探讨了抑制剂与相关淀粉样蛋白生成蛋白之间的分子相互作用。这些相互作用在分子和原子水平上进行了描述，包括共价、非共价和金属介导的机制。作为扩展内容，还总结了体内动物研究和临床试验。为了提高天然产物在体内的生物利用度，还描述了使用纳米载体进行递送的新兴研究工作。最后，展望了此类抑制剂存在的问题和挑战以及未来的发展方向。
