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功能化的聚合物来询问和/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首先，霍乱仍然是一种生命- 流行病每年发病约 290 万例，死亡人数约 95,000 人许多霍乱的爆发可以通过减少细胞结合的治疗来遏制。我们的实验室和合作者证明了霍乱毒素的传播。 B 五聚体 (CTB) 和随机展示半乳糖和岩藻糖自组装成交叉结构的降冰片基聚合物连接的 CTBn-糖聚合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，聚集捕获依赖性分析聚合物结构的动力学和动力学，结合毒性测试，将开发简单的口服其次，大约 12% 的 15-44 岁美国男性不育。或生育力低下，精子无法进行顶体胞吐作用（AE）是很大一部分原因。我们证明人类和小鼠的生育能力低下需要更好的分子诊断。精子顶体胞吐作用 (AE) 被糖聚合物激活，尽管 AE 具有高度协同抑制作用在具有不同主链、糖的聚合物的剂量反应曲线中观察到较高浓度。密度和糖将用于减少抑制臂中的协同性并分析哪些是最好的最有效的探针将用于识别人类 AE 精子受体。第三，具有良好控制的微观结构的共聚物表现出优异的形态和增强的性能，例如空间组织、折叠和自组装，我们证明了精确交替的AB。共聚物可以由双环[4.2.0]辛-6-烯-7-甲酰胺(A)和大的未应变的环烯(B)与Grubbs III催化剂通过交替开环易位聚合反应。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不同 C7 取代基（酮、酯、次甲基）将被用来了解与扩展的 B 单体交替选择性的来源这些 SAR 研究将允许进一步利用 AROMP 进行梯度共聚物合成以进行调整。一锅聚合反应中的材料特性和功能。为这三个独立项目提出的方法与聚合物合成高度相关。预计项目研究人员之间的协同和支持将为创新提供更多机会项目之间的交叉。