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

许多膜蛋白介导细菌致病和宿主相互作用。这些蛋白质不是 更常见的研究渠道，转运蛋白和GPCR，因此，提供了新的知识， 膜蛋白结构、功能和动力学。细菌膜蛋白是抗生素的靶点， 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具有 对治疗递送技术有吸引力的进化功能（例如受体介导的摄取）。这 MIRA应用概述了我们最近在了解几种不同细菌膜方面的努力 蛋白质，以及富有成效的合作桥梁生物物理学不同的生物医学领域。Opa蛋白， 淋病奈瑟菌和淋病奈瑟菌。脑膜炎是与各种宿主受体结合的外膜蛋白 导致细菌被吞噬。这些受体中有几种在癌症中过表达， 为治疗递送提供靶点。了解Opa的结构，动力学和特定相互作用 蛋白质和受体将用于设计靶向脂质体递送至人细胞。我们已经开始 了解Opa的结构，并掌握Opa与受体相互作用的初步数据 CEACAM1.此外，我们已经成功地创建了Opa-脂质体， 吞噬作用未来的方向侧重于多学科的方法来理解的决定因素 基于相互作用的opa-受体选择性和药物递送脂质体的设计。另一 与治疗递送相关的功能是细胞追踪和控制细胞命运。印加，从 衣原体通过与宿主SNARE相互作用，使细菌避开溶酶体， 降解我们提出了各种生物物理和结构的方法来理解结构- 印加的功能关系及其与自身和SNARE的相互作用，以设计细胞内递送 可以避免溶酶体降解的系统。与我们对Opa和印加的研究不同，我们已经开始 研究潜在的抗生素靶点，以帮助对抗耐药细菌的增加。信号肽酶 II，LspA，是一个潜在的目标，因为它是在所有革兰氏阴性细菌中发现的，而不是人类。球霉素 在1978年分离并鉴定了抗生素活性。虽然合成和结构现在 已知球霉素尚未成为治疗剂。我们的目的是探索LspA与 球霉素样肽，以鉴定革兰氏阴性菌的可行抗生素。的结果 该提案提供了关于细菌膜蛋白及其在 使用生物物理方法研究发病机制，并将制定治疗设计策略， 细菌感染和多种涉及CEACAM受体的人类癌症。

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.