Synthesis and chemical biology of inositol phosphate analogues with tuned physicochemical properties

具有调整理化性质的肌醇磷酸类似物的合成和化学生物学

• 批准号: RGPIN-2020-04908
• 负责人: Castagner, Bastien
• 金额: $ 2.62万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=762100
• 关键词: Synthesis; chemical; biology; inositol; phosphate

My research program aims at developing chemical biology tools to study inositol phosphates, an important family of natural small molecules. Inositol phosphates are found ubiquitously in eukaryotic cells where play numerous crucial roles, ranging from cellular signalling and calcium mobilization to regulation of genes. Inositol hexakisphosphate (IP6) is found in high concentrations in cells and act as an important co-factor - an accessory molecule - for many proteins, including foreign proteins such as bacterial toxins and viral coat proteins. IP6 has unique physicochemical properties with a very high negative charge density and strong binding to ions such as calcium, which have complicated its study in complex biological systems. Access to well defined inositol phosphates from natural sources is challenging. Therefore, the chemical synthesis of natural and unnatural inositol phosphate analogs as chemical tools has been essential to unraveling their biological functions. In the past few years, my team and I have developed novel methods to synthesize inositol phosphate analogs with tailored physicochemical properties that suit various applications in biomaterials and as therapeutics. We have notably developed calcium phosphate inorganic nanoparticles coated by inositol phosphate conjugates as gene delivery vehicles in vitro. In addition, we have synthesized novel sulfate and thiophosphate inositol hybrids with altered physicochemical properties. Some of these molecules are currently being explored as therapeutics. The long-term objectives of my research program are first to design and synthesize inositol phosphate analogs as chemical tools to continue unraveling their biological role, and second, to exploit their unique properties to prepare innovative biomaterials and imaging agents. Specifically, we will first harness the calcium phosphate mineral binding properties of inositol phosphates to discover new bones seeking molecules. We will do so by screening a library of closely related molecules to identify the optimal molecule. We will then couple the bone seeking molecule to fluorescent probes that are specifically turned on by the action of enzymes in bone tissues. These innovative probes will illuminate the activity of enzymes that are important in maintaining bone homeostasis in vivo. Finally, we will develop inositol phosphate analogs that will be crucial to discover their putative role in the assembly and maturation of viral particles for multiple members of the retroviruses, including lentiviruses. The importance of inositol phosphates in biology warrants the development of the chemical tools proposed here. Beyond providing essential fundamental knowledge, this research will contribute new functional materials and imaging probes for bone tissues, with potential implications in biomedical implants, gene delivery, and novel diagnostic tools for bone disorders.

我的研究项目旨在开发化学生物学工具来研究磷酸肌醇（一个重要的天然小分子家族）。肌醇磷酸普遍存在于真核细胞中，在其中发挥许多关键作用，从细胞信号传导和钙动员到基因调控。肌醇六磷酸（IP 6）在细胞中以高浓度存在，并作为许多蛋白质的重要辅因子-辅助分子，包括细菌毒素和病毒外壳蛋白等外源蛋白。IP 6具有独特的物理化学性质，具有非常高的负电荷密度和与钙等离子的强结合，这使其在复杂生物系统中的研究变得复杂。从天然来源获得定义明确的肌醇磷酸盐具有挑战性。因此，作为化学工具的天然和非天然肌醇磷酸类似物的化学合成对于揭示其生物学功能至关重要。在过去的几年里，我和我的团队开发了新的方法来合成肌醇磷酸类似物，这些类似物具有定制的物理化学性质，适合生物材料和治疗学中的各种应用。我们已经开发了磷酸肌醇复合物包覆的磷酸钙无机纳米粒子作为体外基因传递载体。此外，我们已经合成了新的硫酸酯和硫代磷酸肌醇杂化物，改变了理化性质。其中一些分子目前正在探索作为治疗剂。我的研究计划的长期目标是首先设计和合成肌醇磷酸类似物作为化学工具，继续解开他们的生物作用，第二，利用其独特的性能，以制备创新的生物材料和成像剂。具体来说，我们将首先利用磷酸肌醇的磷酸钙矿物质结合特性来发现新的骨寻找分子。我们将通过筛选密切相关的分子库来确定最佳分子。然后，我们将把寻骨分子偶联到荧光探针上，这些荧光探针通过骨组织中酶的作用而特异性地打开。这些创新的探针将阐明酶的活性，这些酶对维持体内骨稳态很重要。最后，我们将开发肌醇磷酸类似物，这对于发现它们在逆转录病毒（包括慢病毒）的多个成员的病毒颗粒组装和成熟中的假定作用至关重要。肌醇磷酸在生物学中的重要性保证了这里提出的化学工具的发展。除了提供必要的基础知识外，这项研究还将为骨组织提供新的功能材料和成像探针，在生物医学植入物，基因递送和骨骼疾病的新型诊断工具方面具有潜在的意义。