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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.

我们的实验室将使用基于以下条件的功能化聚合物来研究和/或阻断生物系统中的功能我们实验室的最新进展为如何控制结合和激活提供了见解受体，并控制Ru催化的易位共聚。首先，霍乱仍然是一种生命-- 威胁疾病，每年在地方病中发病率约290万例，死亡约9.5万人国家。许多霍乱的爆发可以通过一种减少细胞结合的疗法来阻止，因此霍乱弧菌的传播，霍乱的病原体。我们的实验室和合作者证明了霍乱毒素 B五聚体(CTB)和降冰片基聚合物随机显示半乳糖和岩藻糖自组装成交叉- 连接的CTBn-糖共聚物网络。更大的聚集体可以更好地抑制霍乱中毒。不同岩藻糖/半乳糖聚合物体系的合成及聚集态捕获的相关性分析和聚合物结构的动力学，结合毒性测试，将开发出简单的，口服的霍乱治疗学。其次，在15-44岁的美国男性中，约有12%患有不育症精子顶体胞吐功能障碍(AE)是导致精子不育或不育的重要原因。为了诊断不育症，需要更好的分子诊断方法。我们证明了人类和老鼠精子顶体胞吐功能(AE)可被糖基聚合物激活，但高度协同抑制AE 在较高浓度下观察到剂量-反应曲线。具有不同主链、糖的聚合物密度和糖将被用来降低抑制臂中的协作性，并分析哪些是最好的用于激活人类声发射。最有效的探针将用于识别人类AE精子受体。第三，微观结构可控的共聚物表现出优异的形态和增强的性能，如空间组织、折叠、自组装等。我们证明了精确交替的AB 双环[4.2.0]辛基-6-烯-7-羧胺(A)和大分子无张力共聚物通过交替开环歧化聚合，在GRubbs III催化剂上合成环烯(B)。A级单体取代基和聚合物的微序列定义了表面行为和溶液结构形态特征。不同C7取代基(酮、酯、亚甲基)，以了解与膨胀的B单体交替选择性的来源曲目。这些合成孔径雷达研究将使进一步开发用于梯度共聚合成的AROMP进行调整一锅聚合反应中的材料性质和功能。潜在的化学合成为这三个独立项目提出的方法通过聚合物合成高度相关。我们预计项目研究人员之间的协同和支持将提供进一步的创新机会项目之间的交叉。