Biophysical understanding of pathogen-host membrane protein interactions for drug discovery and delivery

许多膜蛋白参与细菌的致病过程和宿主间的相互作用。这些蛋白质不是 更常被调查的通道、传输器和GPCR，因此提供了关于 膜蛋白的结构、功能和动力学。细菌膜蛋白是抗生素治疗的靶点 这种抵抗是一个巨大的威胁。此外，与宿主相互作用的细菌膜蛋白有 对治疗性递送技术有吸引力的进化功能(例如，受体介导的摄取)。这 MIRA应用概述了我们在理解几种不同细菌膜方面的最新努力 蛋白质，以及卓有成效的合作，将生物物理学与不同的生物医学领域联系起来。OPA蛋白来自 淋病奈瑟菌和脑膜炎奈瑟菌是外膜蛋白，可与多种宿主受体结合。 这会导致细菌被吞噬。其中几种受体在癌症中过度表达，并可能 为治疗提供目标。了解OPA的结构、动力学和特定的交互作用 蛋白质和受体将被用来设计定向脂质体输送到人类细胞。我们已经开始 了解Opa的结构，并对Opa与受体之间的相互作用有初步的数据 CEACAM1。此外，我们还成功地创造了诱导受体介导的Opa-脂质体。 吞噬作用。未来的方向集中在用多学科的方法来理解 OPA受体选择性和基于相互作用的工程化治疗性给药脂质体。另一个 对治疗传递感兴趣的功能是细胞跟踪和控制细胞命运。印加，来自 衣原体，劫持通过与宿主陷阱相互作用来宿主贩运，从而使细菌避免溶酶体 退化。我们提出了各种生物物理和结构方法来理解结构- 印加的功能关系及其与自身和陷阱的相互作用以设计细胞内给药 可以避免溶酶体降解的系统。与我们对Opa和Inca的研究不同，我们已经开始 调查潜在的抗生素靶点，以帮助抗击耐药细菌的增加。信号肽酶 II，LspA，是一个潜在的靶标，因为它在所有革兰氏阴性细菌中都存在，而不是在人类中。球菌素 并于1978年对其进行了抗菌活性鉴定。虽然现在合成和结构都是 众所周知，球霉素还没有成为一种治疗药物。我们旨在探索LspA与LspA的结合和抑制作用 球霉素样肽，以确定对革兰氏阴性菌可行的抗生素。这样做的结果 提案提供了关于细菌膜蛋白及其在 使用生物物理方法的发病机制，并将为治疗药物的设计开发策略 细菌感染和多种与CEACAM受体有关的人类癌症。

Many membrane proteins mediate bacterial pathogenesis and host interactions. These proteins are not the more commonly investigated channels, transporters, and GPCRs and, therefore, provide new knowledge about membrane protein structure, function, and dynamics. Bacterial membrane proteins are targets of antibiotics for which resistance is a great threat. In addition, bacterial membrane proteins that interact with hosts have evolved functions that are attractive to therapeutic delivery technologies (e.g. receptor-mediated uptake). This MIRA application outlines our recent endeavors in understanding several different bacterial membrane proteins, as well as, fruitful collaborations bridging biophysics to different biomedical fields. Opa proteins from Neisseria gonorrhoeae and N. meningitidis are outer membrane proteins that bind to various host receptors that induce engulfment of the bacterium. Several of these receptors are overexpressed in cancers and may provide a target for therapeutic delivery. Knowledge of the structure, dynamics, and specific interactions of Opa proteins and receptors will be used to design targeted liposome delivery to human cells. We have begun to understand the Opa structure and have preliminary data on the interactions between Opa and the receptor CEACAM1. In addition, we have successfully created Opa-liposomes that induce receptor-mediated phagocytosis. Future directions focus on a multidisciplinary approach to understanding the determinants of Opa-receptor selectivity and engineer therapeutic delivery liposomes based on the interaction. Another function of interest to therapeutic delivery, is cellular tracking and controlling cellular fate. IncA, from Chlamydiae, hijacks host trafficking by interacting with host SNAREs allowing the bacterium to avoid lysosomal degradation. We propose a variety of biophysical and structural approaches to understanding the structure- function relationship of IncA and interactions with itself and SNAREs in order to design intracellular delivery systems that can avoid lysosomal degradation. Distinct from our research with Opa and IncA, we have begun to investigate potential antibiotic targets to help combat the increase in resistant bacteria. The signal peptidase II, LspA, is a potential target because it is found in all Gram-negative bacteria and not humans. Globomycin was isolated and the antibiotic activity was identified in 1978. Although the synthesis and structure are now known, globomycin has not become a therapeutic. We aim to explore the binding and inhibition of LspA with globomycin-like peptides in order to identify viable antibiotics for Gram-negative bacteria. The results of this proposal with provide unique knowledge and insights about bacterial membrane proteins and their roles in pathogenesis using biophysical approaches and will develop strategies for the design of therapeutics to treat bacterial infections and a variety of human cancers involving CEACAM receptors.