Turnkey THz Spectroscopy/Polarimetry System for Pharmaceutical Applications

适用于制药应用的交钥匙太赫兹光谱/旋光测量系统

基本信息

批准号：
9410374
负责人：
Vladimir Kozlov
金额：
$ 21.68万
依托单位：
MICROTECH INSTRUMENTS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2019-07-31
项目状态：
已结题

项目摘要

ABSTRACT / SUMMARY The outcome of this phase 1 project will yield a turnkey system for spectroscopy/polarimetry in the terahertz (0.8-3.0 THz) frequency range, designed to support development of new drugs. This system will directly probe protein vibrations using polarized terahertz radiation, allowing researchers to rapidly characterize intramolecular vibrations, which will help identify sites on proteins for potential drug targets. By looking at differences in absorption of polarized light between different relative molecular orientations, vibrational resonances can be isolated from the isotropic background which generally obscure these features. This measurement system will enable a researcher to readily mount a protein microcrystal and immediately have the intramolecular vibrational fingerprint to readily see if and how this fingerprint has changed with single point mutations or binding. This characterization of intramolecular dynamics will be done without the need to introduce an external tag to the system under study. The main technological hurdle that will be addressed during this phase I project that will be crucial to the commercialization is the vast simplification of the data acquisition. A high brightness terahertz source will be developed that will allow intensity based detection of the spectroscopic data. This source will use a high power fiber laser and a quasi-phase matched nonlinear crystal to generate tunable, narrowband terahertz output. The second technological improvement will be the development of polarization control module, which will allow data acquisition without moving the sample, which is necessary for fast data collection. Finally, an integrated sample holder/detection module will be developed that allows users to easily change samples without disturbing the alignment into the detector. Information on long range structural vibrations is of particular interest in design of allosteric drugs, which bind to a location distant from the active site on a molecule. The current interest in allosteric drugs is due to their distinct advantages over orthosteric drugs (drugs that bind directly to the active site). Currently there are research efforts dedicated to gaining a better fundamental understanding of the mechanisms behind allostery, with the goal of eventually predicting how action at distant sites modulates protein activity. This information will stream line drug discovery efforts, reduce costs for the drug industry and cost of medications for the patients. More importantly, it will have a much broader societal impact by expediting the drug discovery process and making new drugs available faster.

摘要/总结该第一阶段项目的成果将产生一个用于光谱/偏振测定的交钥匙系统太赫兹（0.8-3.0 THz）频率范围，旨在支持新药的开发。该系统将直接使用偏振太赫兹辐射探测蛋白质振动，使研究人员能够快速表征分子内振动，这将有助于识别蛋白质上潜在药物靶标的位点。通过查看不同相对分子取向之间的偏振光吸收差异，振动共振可以从各向同性背景中分离出来，而各向同性背景通常会掩盖这些特征。这测量系统将使研究人员能够轻松安装蛋白质微晶并立即获得分子内振动指纹，可轻松查看该指纹是否以及如何单点改变突变或结合。这种分子内动力学的表征无需引入正在研究的系统的外部标签。第一阶段项目将解决的主要技术障碍对于商业化是数据采集的极大简化。高亮度太赫兹源将是开发出能够基于强度检测光谱数据的技术。该源将使用高功率光纤激光器和准相位匹配非线性晶体产生可调谐、窄带太赫兹输出。这第二项技术改进将是偏振控制模块的开发，这将使数据无需移动样品即可进行采集，这是快速数据采集所必需的。最后是一个综合样本将开发支架/检测模块，允许用户轻松更换样品而不干扰样品对准检测器。关于长程结构振动的信息在变构药物的设计中特别令人感兴趣，这结合到远离分子活性位点的位置。目前对变构药物的兴趣是由于它们与正构药物（直接与活性位点结合的药物）相比具有明显的优势。目前有研究努力致力于更好地了解变构背后的机制，最终预测远距离位点的作用如何调节蛋白质活性的目标。此信息将流式传输协调药物发现工作，降低制药行业的成本和患者的药物成本。更多的重要的是，它将通过加快药物发现过程并使其产生更广泛的社会影响新药上市速度更快。