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

我的研究项目旨在开发化学生物学工具来研究磷酸肌醇，这是一种重要的天然小分子家族。肌醇磷酸盐普遍存在于真核细胞中，在细胞信号传导、钙动员和基因调控等方面发挥着重要作用。肌醇六肌磷酸（IP6）在细胞中含量很高，是许多蛋白质的重要辅助因子——辅助分子，包括细菌毒素和病毒外壳蛋白等外来蛋白质。IP6具有独特的物理化学性质，具有很高的负电荷密度和与钙等离子的强结合，使其在复杂生物系统中的研究变得更加复杂。从天然来源获得明确定义的肌醇磷酸是具有挑战性的。因此，化学合成天然和非天然磷酸肌醇类似物作为化学工具对揭示其生物学功能至关重要。

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.