Polymer Approaches to Receptor Activation and Inhibition

受体激活和抑制的聚合物方法

基本信息

批准号：
10795136
负责人：
NICOLE S SAMPSON
金额：
$ 6.48万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

项目摘要

Our laboratory will interrogate and/or block function in biological systems with functionalized polymers based on recent developments from our laboratory that provide insights into how to control binding and activation of receptors, and into control of ruthenium-catalyzed metathesis copolymerizations. First, cholera is still a life- threatening illness with an annual incidence of ~2.9 million cases and ~95,000 deaths annually in endemic countries. Many outbreaks of cholera would be staunched by a therapeutic that reduced cell binding and thus spreading of V. cholerae, the etiologic agent. Our laboratory and collaborators demonstrated that cholera toxin B pentamer (CTB) and a norbornyl polymer randomly displaying galactose and fucose self-assemble into cross- linked CTBn–glycopolymer networks. Larger aggregates result in better inhibition of cholera intoxication. Synthesis of different fucose/galactose polymer systems, analysis of the dependence of aggregation capture and kinetics on polymer structure, in combination with toxicity testing will be undertaken to develop simple, oral therapeutics for cholera disease. Second, about 12% of American males between the ages of 15-44 are infertile or subfertile, and failure of sperm to undergo acrosomal exocytosis (AE) is responsible for a significant fraction. Better molecular diagnostics are required to diagnose subfertility. We demonstrated that human and mouse sperm acrosomal exocytosis (AE) are activated with glycopolymers, although highly cooperative inhibition of AE is observed at higher concentrations of the dose-response curve. Polymers with different backbones, sugar densities, and sugars will be utilized to reduce cooperativity in the inhibition arm and to analyze which are best for activation of human AE. The most effective probes will be used to identify the human AE sperm receptor. Third, copolymers with well-controlled microstructure display superior morphology and enhanced properties, such as spatial organization, folding and self-assembly. We demonstrated that precisely alternating AB copolymers can be prepared from bicyclo[4.2.0]oct-6-ene-7-carboxamides (A) and large unstrained cycloalkenes (B) with Grubbs III catalyst through alternating ring-opening metathesis polymerization. The A monomer substituent and the microsequence of the polymer define surface behavior and solution structure morphologies. Mechanistic structure-activity studies with A monomer varying C7 substituents (ketone, ester, methenyl) will be undertaken to understand the source of alternating selectivity with an expanded B monomer repertoire. These SAR studies will allow further exploitation of AROMP for gradient copolymer synthesis to tune material properties and functions in one-pot polymerization reactions. The underlying chemical synthetic methodologies proposed for these three discrete projects are highly related through polymer synthesis. We anticipate synergy and support between project researchers will provide further opportunities for innovation that cross between projects.

我们的实验室将在具有基于功能化聚合物的生物系统中询问和/或块功能我们实验室的最新发展提供了有关如何控制结合和激活的见解受体，并控制芳族催化的分解共聚。首先，霍乱仍然是一种生活 - 每年发生约290万例病例和约95,000例死亡的疾病国家。许多霍乱爆发会被降低细胞结合的治疗性粘住，从而粘贴病因学V. Cholerae的传播。我们的实验室和合作者证明了霍乱毒素 b五聚体（CTB）和一个随机表现出半乳糖和富藻糖自组装成跨的聚合物链接的CTBN - 聚聚合物网络。较大的聚集体会更好地抑制霍乱中毒。不同的岩藻/半乳糖聚合物系统的合成，分析聚集捕获的依赖性将进行有关聚合物结构的动力学，结合毒性测试，以发展简单的口服治疗霍乱疾病。其次，约有12％的美国男性在15-44岁之间不育或副胞外胞胞菌病（AE）的次级和精子的未能造成显着份量。需要更好的分子诊断才能诊断出差。我们证明了人和老鼠精子丙学生胞吐作用（AE）被糖聚合物激活，尽管高度合作抑制AE 在较高浓度的剂量反应曲线下观察到。聚合物具有不同的骨架，糖密度和糖将用于减少抑制臂中的协调，并分析哪些是最好的激活人AE。最有效的问题将用于识别人AE精子受体。第三，具有良好控制的微结构的共聚物表现出较高的形态和增强的性质，例如空间组织，折叠和自组装。我们证明了精确交替的AB 可以从Bicyclo [4.2.0] Oct-6-Ene-7-羧酰胺（A）和大型未经培养的共聚物制备共聚物通过改变打环的分解聚合的催化剂的环烷烃（B）。 a 单体亚辅导和聚合物的微钉定义表面行为和溶液结构形态。机械结构活性研究，单体变化的C7亚探测器（Ketone，Ester，将甲烯基）通过扩展的B单体来理解替代选择性的来源曲目。这些SAR研究将允许进一步利用AROMP以调整梯度共聚物合成一锅聚合反应中的材料特性和功能。基础化学合成针对这三个离散项目提出的方法通过聚合物合成高度相关。我们预期项目研究人员之间的协同作用和支持将为创新提供进一步的机会在项目之间交叉。