DRUG DISCOVERY AND DIAGNOSTICS BY FORCE SPECTROSCOPY

通过力谱进行药物发现和诊断

• 批准号: 2718064
• 负责人: RAJ K LARTIUS
• 金额: $ 9.97万
• 依托单位: BIOFORCE NANOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2718064
• 关键词: alkyltransferase; antineoplastics; atomic force microscopy; bioengineering /biomedical engineering; biomedical equipment development; biosensor device; carcinogenesis inhibitor; crosslink; diagnosis design /evaluation; drug screening /evaluation; enzyme inhibitors; guanine nucleotide binding protein; guanosine triphosphate; guanosinetriphosphatase activating protein; intermolecular interaction; method development; mutant; neoplasm /cancer chemotherapy; neoplasm /cancer diagnosis; prodrugs; spectrometry

The goal of this SBIR Phase I proposal is to develop force spectroscopy (F-SPEC) as a tool for drug discovery and high throughput molecular screening and analysis. F-SPEC is based on direct measurement of molecular interactions using an ultra-sensitive biosensor created by biomolecular functionalization of an Atomic Force Microscope (AFM) probe. Phase I will focus on the G-protein Ras, a key protein in 30% of all cancers. Farnesylation of Ras is required before it can associate with the membrane for signal transduction, making competitive inhibitors of farnesyl transferase (FT,) attractive as cancer fighting drugs. Specific Aim 1 is to show by F-SPEC that a difference in the interaction between Ras and farnesyl transferase (FTase) can be measured while an inhibitor is present versus absent Abnormal Ras GTPase activity is often related to mutations involved in oncogenesis. Specific Aim 2 is to develop a method using F-SPEC to distinguish wild-type from mutant Ras based upon binding interactions with GTPase Activating Proteins (GAPs) in the presence or absence of GTP. If Phase I is successful, F-SPEC will be implemented as a high throughput drug discovery and molecular diagnostic technology in Phase II and beyond. PROPOSED COMMERCIAL APPLICATIONS: The technology to be developed in this research program will provide a rapid and ultra-sensitive method for screening potentially useful compounds as drugs, and for testing differences in wt and mutant gene products involved in cancer and other diseases.

该SBIR I期建议的目的是发展力光谱 （F-Spec）作为药物发现和高通量分子的工具 筛选和分析。 F-Spec基于直接测量 使用由超敏感生物传感器产生的分子相互作用 原子力显微镜（AFM）探针的生物分子官能化。 第一阶段将重点关注G蛋白RA，这是30％的关键蛋白 癌症。需要拉斯的法尼化，然后才能与 信号转导的膜，使得竞争性抑制剂 Farnesyl转移酶（FT）作为抗癌药物的吸引力。具体的 AIM 1是通过F-Spec表明相互作用之间的差异 可以在抑制剂时测量Ras和Farnesyl转移酶（FTase） 存在与不存在异常RAS GTPase活性通常是相关的 涉及肿瘤发生的突变。特定目标2是开发 使用F-Spec的方法将野生型与基于突变的RAS区分开 与GTPase激活蛋白（GAP）的结合相互作用 GTP的存在或不存在。如果第一阶段成功，F-Spec将是 以高吞吐药物发现和分子诊断为实施 第二阶段及以后的技术。 拟议的商业应用： 该研究计划中要开发的技术将提供 快速和超敏感的方法，用于筛选潜在有用的 作为药物的化合物，用于测试WT和突变基因的差异 涉及癌症和其他疾病的产品。