Artificial Antibody Mimetics

人工抗体模拟物

• 批准号: 7062445
• 负责人: JOHN A ZEBALA
• 金额: --
• 依托单位: SYNTRIX BIOSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-13 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7062445
• 关键词: Affinity; Antibodies; Basic Science; Binding; Biological Assay; Biology; Bypass; Characteristics; Chemicals; Chimera organism; Collection; Cultured Cells; DNA; Detection; Diagnostic; Diagnostics Research; Disadvantaged; Enzymes; Exhibits; Genes; Growth; Hybridomas; Letters; Libraries; Malignant - descriptor; Malignant Neoplasms; Methods; Movement; Numbers; Pathway interactions; Peptide Library; Peptides; Performance; Phage Display; Pharmaceutical Preparations; Phase; Phosphopeptides; Phosphoproteins; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Phosphotyrosine; Physiological; Population; Principal Investigator; Protein Dephosphorylation; Protein Kinase; Proteins; Research; Ribosomes; Risk; Screening procedure; Signal Transduction; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Source; Specificity; Staging; System; Technology; Time; aptamer; combinatorial; combinatorial chemistry; cost; design; drug discovery; genetic regulatory protein; interest; mammalian genome; member; mimetics; novel; programs; tool

DESCRIPTION (provided by applicant): Among the many mechanisms by which cancer arises, it is now appreciated that inappropriate phosphorylation is a key pathway. Detection agents capable of binding discrete phosphoproteins with high specificity will be important tools for research, diagnostics, and drug discovery. Currently available detection agents are most commonly antibodies or antibody mimetics made using biologic or enzymatic systems. Detection agents that rely on biology or enzymes suffer from several inherent shortcomings that include a restricted biomolecule repertoire that is time-consuming and costly to manufacture. Syntrix proposes to develop a MetaMorph technology that completely bypasses biologic and enzymatic sources with novel synthetic mimetics comprising PNA-cyclopeptide heterotetramers. MetaMorphs will be identified using a novel and purely chemical discovery paradigm termed PNA-display. We hypothesize that PNA-display will permit us to screen very large heterotetramer populations and identify at least moderate- to high-affinity mimetics in a facile system. High-affinity MetaMorphs will provide a phosphoprotein detection capability equivalent to that of antibodies and other biologically derived mimetics, but without the disadvantages. The SBIR Phase I proposal is designed to prove the feasibility of using PNA-display to identify at least moderate affinity MetaMorphs. Demonstrating feasibility will set the stage to move into an aggressive Phase II program to develop high-affinity MetaMorphs capable of detecting phosphotyrosine embedded within peptides having numerous different primary sequences. Such a MetaMorph collection will be capable of detecting hundreds of known and unknown phosphoproteins and will be of significant utility in basic science, diagnostics, and efforts to develop drugs that modulate protein kinases and phosphatases.

描述（由申请人提供）： 在癌症发生的许多机制中，现在认识到不适当的磷酸化是一个关键途径。能够以高特异性结合离散磷蛋白的检测剂将是研究、诊断和药物发现的重要工具。目前可用的检测剂最常见的是使用生物或酶系统制备的抗体或抗体模拟物。依赖于生物学或酶的检测剂具有几个固有的缺点，包括制造耗时且成本高的受限生物分子库。Synonymous提出开发一种MetaMorph技术，该技术完全绕过生物和酶源，具有包含PNA-环肽异源四聚体的新型合成模拟物。MetaMorphs将使用称为PNA展示的新的纯化学发现范式进行鉴定。我们假设PNA展示将允许我们筛选非常大的异源四聚体群体，并在一个简单的系统中识别至少中等至高亲和力的模拟物。高亲和力MetaMorphs将提供与抗体和其他生物衍生的模拟物相当的磷蛋白检测能力，但没有缺点。SBIR第一阶段提案旨在证明使用PNA展示来识别至少中等亲和力的元形态的可行性。证明可行性将为进入积极的第二阶段计划奠定基础，以开发能够检测嵌入具有许多不同一级序列的肽中的磷酸酪氨酸的高亲和力MetaMorphs。这样的MetaMorph集合将能够检测数百种已知和未知的磷蛋白，并且将在基础科学、诊断和开发调节蛋白激酶和磷酸酶的药物的努力中具有重要的实用性。