Cationic Amphiphilic Polyproline Helices for Cell Penetration

生命过程化学项目支持普渡大学的Jean Chmielewski教授开发用于穿透选择性细胞的阳离子两亲性聚脯氨酸螺旋。由于基因、多肽、颗粒和小分子不能充分地穿过膜双分子层，因此它们被禁止被动地吸收到细胞中。PI的小组设计了一类分子，阳离子两亲性聚脯氨酸螺旋（CAPHs），已被证明可以有效地穿过细胞膜并选择性地进入某些细胞。本研究的目标是利用合成化学和膜生物化学（模型和细胞）的工具，探索CAPHs中允许有效细胞摄取的特定结构特征，并利用CAPHs显著的细胞穿透特性在细胞内运送货物。考虑到这些目标，将解决的具体问题包括：(1)CAPHs的哪些特征可以被修改以促进膜穿透和特异性？(2) CAPHs与脂质双分子层相互作用并穿越细胞膜的机制是什么？(3)哪些小分子荧光团可以通过与低聚CAPHs的非共价结合进入细胞？高阳离子分子穿越疏水细胞膜的能力是非常令人兴奋的，并将对许多科学领域产生广泛的影响，包括纳米技术、基因治疗、药物输送和基本的膜生物化学。随着PI继续推进阳离子两亲体/膜相互作用的知识基础，她将通过撰写该领域的综合评论来接触其他科学学科，并将参加更多的公共论坛，与非科学家分享结果和观点。这一研究领域——将化学和生物学结合起来——也将产生广泛的影响，为年轻学生接触科学的跨学科方面奠定基础。考虑到这一点，PI制定了一项针对高中学生及其教师的外展计划。这些拓展工作的目标是让印第安纳州的一大批高中学生和教师通过真正的动手接触，学会欣赏现代科学学科的重叠。这些研究的目标是开发分子可以进入细胞的载体。最终，这项工作将导致对如何将治疗、诊断工具和探针引入特定细胞的更深入理解。

The Chemistry of Life Processes program supports Professor Jean Chmielewski at the Purdue University in developing cationic amphiphilic polyproline helices for penetrating selective cells. The passive uptake of genes, polypeptides, particles and, at times, small molecules into cells is prohibited due to their inability to adequately cross the membrane bilayer. The PI's group has designed a class of molecules, cationic amphiphilic polyproline helices (CAPHs), that have been shown to effectively cross the cell membrane and enter certain cells selectively. The goals of the proposed research seek to explore specific structural features within CAPHs that allow for efficient cell uptake using the tools of synthetic chemistry and membrane biochemistry (model and cellular), and to harness the remarkable cell penetrating characteristics of CAPHs for the delivery of cargo within the cell. With these goals in mind, the specific questions that will be addressed include: (1) What features of CAPHs may be modified to promote membrane penetration and specificity? (2) What is the mechanism used by CAPHs to interact with the lipid bilayer and to cross cellular membranes? (3) What small molecule fluorophores may be imported into cells through non-covalent association with oligomeric CAPHs?The ability of highly cationic molecules to cross the hydrophobic cell membrane is unusually evocative and would have a broad impact on many areas of science, including nanotechnology, gene therapy, drug delivery, and basic membrane biochemistry. As the PI continues to advance the knowledge base of cationic amphiphile/membrane interactions, she will reach out to other scientific disciplines by writing comprehensive reviews of the area and will participate in more public forums to share results and perspectives with non-scientists. This area of research--combining chemistry and biology--also would have broad impact as the foundation for exposure to interdisciplinary aspects of science to younger students. With this in mind, the PI has developed an outreach program targeting high school students and their teachers. It is the goal of these outreach efforts that a significant group of Indiana high school students and teachers will learn to appreciate the overlap of modern scientific disciplines through true hands-on exposure.These studies are directed at the development of shuttles with which molecules can enter cells. Ultimately this work will lead to a deeper understanding of how to bring therapies, diagnostic tools and probes into specific cells.