Cationic Amphiphilic Polyproline Helices (CAPHs): Coupling Antibacterial Activity with Mammalian Cell Penetration

有了这个奖项，化学部的生命过程化学项目将资助普渡大学的Jean Chmielewski教授研究新设计的细胞穿透化合物是如何起作用的。由于基因、蛋白质、颗粒和小分子无法充分穿过细胞膜，因此它们无法进入细胞。一类分子已经被设计出来，可以有效地穿过细胞膜进入人体细胞。这些分子也会与细菌细胞相互作用，导致细菌死亡。在这项工作中，对分子的改变是为了改善这两种活动，同时也为了更深入地了解分子的功能方式。这种追求使研究生能够获得有机和肽合成，人类细胞成像和抗菌作用方面的专门训练。该项目还旨在通过化学多样性计划增加普渡大学化学系研究生人数的多样性，这是一个三管齐下的计划，旨在成功招募、保留和专业发展代表性不足的少数民族研究生。本研究项目进行了一类分子的机制研究，阳离子两亲性聚脯氨酸螺旋（CAPHs），被设计用于有效地转移哺乳动物细胞膜，并显示出强大的抗菌活性。本研究的目标是探索CAPH中允许有效细胞摄取、亚细胞定位和抗菌作用的特定结构特征，同时建立CAPH活性的机制模型。此外，caph被用来改变抗生素的特异性，如万古霉素，以靶向革兰氏阴性细菌。这项研究的信息为哺乳动物和细菌细胞中CAPHs的结构和功能提供了更深入的机制见解。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Professor Jean Chmielewski from Purdue University to investigate how newly designed cell penetrating compounds function. The entry of genes, proteins, particles and, at times, small molecules into cells is prohibited due to their inability to adequately cross the membrane of cells. A class of molecules has been designed that effectively cross the cell membrane and enter human cells. These same molecules also interact with bacterial cells leading to the death of the bacteria. In this work, changes to the molecules are made to improve both of these activities, and also to gain a deeper understanding of the way in which the molecules function. This pursuit allows graduate students to acquire specialized training in organic and peptide synthesis, human cell imaging and antibacterial action. This project also seeks to increase the diversity of the graduate student population in the chemistry department at Purdue University through the Chemistry Diversity Initiative, a three-pronged program for the successful recruitment, retention and professional development of underrepresented minority graduate students.This research project undertakes mechanistic studies of a class of molecules, cationic amphiphilic polyproline helices (CAPHs), that are designed to effectively translocate mammalian cell membranes and also display potent antibacterial activity. The goals of the proposed research are to probe the specific structural features within CAPHs that allow for efficient cell uptake, subcellular localization and antibacterial action, while developing a mechanistic model for CAPH activity. Additionally, CAPHs are harnessed to alter the specificity of antibiotics, such as vancomycin, to target Gram negative bacteria. Information from this study provides a deeper mechanistic insight into the structure and function of CAPHs within mammalian and bacterial cells.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.