Helical aromatic foldamer-based protein recognition

蛋白质-蛋白质和蛋白质-核酸相互作用（PPI和PNI）是调节细胞生命所必需的。这些相互作用的抑制剂为治疗应用提供了有用的药理学工具和候选物。然而，PPI或PNI涉及大的分子表面积，这使得药物样小分子难以充当有效的抑制剂。通过选择技术鉴定的人工蛋白质或人工核酸足够大并且构成合适的PPI或PNI抑制剂，但是它们缺乏合成分子的一些优点，特别是它们的结构和代谢稳定性。我们的研究小组一直在探索一种替代方法，它结合了小分子和人工蛋白质的一些优点：设计大蛋白质大小的合成分子，采用稳定的螺旋结构（“折叠体”），并选择性地识别和结合蛋白质靶点。最近的发展包括模拟B-DNA负电荷表面并抑制一些PNI的折叠体的设计，以及证明短折叠体作为核糖体体外肽翻译的引发剂是耐受的。在这个项目中，我们建议利用这些发现的分子识别蛋白质的重要性表观遗传学。表观遗传学是一个不断发展的领域，关注细胞分裂过程中传递的特征和功能，这些特征和功能不是在遗传物质本身中编码的。我们的目标是：1）破译折叠体DNA电荷表面模拟物与参与DNA包装的蛋白质之间相互作用的结构基础2）研究DNA模拟折叠体如何改变染色质组装，并鉴定与基于折叠体的DNA模拟物结合比与DNA结合更好的染色质蛋白; 3）鉴定与表观遗传过程中涉及的蛋白质结合的杂合折叠体-肽大环化合物，阐明所涉及的相互作用的结构基础;并使用该知识来改善其性质。

Protein-protein and protein-nucleic acid interactions (PPIs and PNIs) are required for the regulation of cellular life. Inhibitors of these interactions provide useful pharmacological tools and candidates for therapeutic applications. However, PPIs or PNIs involve large molecular surface areas which makes it difficult for drug-like small molecules to act as efficient inhibitors. Artificial proteins or artificial nucleic acids identified by selection technologies are large enough and constitute suitable PPI or PNI inhibitors but they lack some advantages of synthetic molecules in particular their structural and metabolic stability. Our research group has been exploring an alternate approach that combines some benefits of both small molecules and artificial proteins: the design of large - protein-sized - synthetic molecules that adopt stable helical structures ("foldamers") and that selectively recognize and bind protein targets. Recent developments include the design of foldamers that mimic the B-DNA negative charge surface and inhibit some PNIs as well as the demonstration that short foldamers are tolerated as initiators for in vitro peptide translation by the ribosome. In this project, we propose to exploit these findings for the molecular recognition of proteins of importance in epigenetics. Epigenetics is a growing field concerned with characteristics and functions transmitted during cell division that are not encoded in the genetic material itself. Our objectives are: 1) to decipher the structural basis of interactions between the foldamer DNA charge surface mimics and proteins involved in DNA packaging (chromatin) and thereby establish a firm basis for structure-based foldamer-design; 2) to investigate how DNA-mimic foldamers may alter chromatin assembly and identify chromatin proteins that bind to the foldamer-based DNA mimics better than to DNA; 3) to identify hybrid foldamer-peptide macrocycles that bind to proteins involved in epigenetic processes, elucidate the structural basis of the interactions involved; and use that knowledge to improve their properties.