Supramolecular Approaches to Protein Inhibitors Activated by MicroRNA-21

MicroRNA-21 激活蛋白质抑制剂的超分子方法

基本信息

项目摘要

DESCRIPTION (provided by applicant): Prodrugs that are triggered by cancer biomarkers are attractive because of their potential to be activated preferentially in cancer cells thereby reducing the serious adverse effects associated with conventional chemotherapy. While numerous cancer biomarkers have been discovered, prodrugs triggered by enzymes have been the main focus because enzymes can activate prodrugs via covalent transformations. Thus, a barrier exists in using non-enzyme biomarkers for prodrug-activation because of our poor understanding of how to develop molecules that selectively recognize, and are activated by, biomarkers that cannot facilitate covalent transformations. The existence of this knowledge gap hinders the full scope of prodrugs that can be developed. Thus the long-term vision of this project is to generate non-covalently triggered prodrugs. The objective of this basic-science application, which is a seminal step in achieving our long term goal, is to establish fundamental supramolecular mechanisms for the non-covalent activation of protein inhibitors by microRNA-21 (miR-21), a highly deregulated, oncogenic, miR. The central hypothesis of this application, which we will test via two complementary design strategies (Aim 1 and 2, respectively), is that miR-21 inducible protein antagonists can be achieved by developing DNA-small molecule chimeras (DCs), that undergo a structural switch from a de-activated conformation to an activated state upon binding sequence specifically to miR-21. The specific aims for this project are to develop, (Aim 1) hairpin-forming DCs de-activated by host/guest interactions and (Aim 2) bidentate DCs de-activated via duplex formation with a guide strand, as miR-21 responsive inhibitors of clinically relevant carbonic anhydrase-II (CA-II). In both aims, we will synthesize and characterize the respective DC systems and will probe their ability to undergo miR-21 induced structure-switching to an activated state via a number of spectroscopic experiments (including UV-vis and fluorescence quenching). Subsequently, the differential ability of the de-activated and active DC conformations to inhibit CA-II will be evaluated (via a colorimetric esterase assay). After optimization of the structure of the DC systems (including enhancing CA-II binding and nuclease resistance), we will transfect DCs into cell-lines over expressing (and control cell-lines under expressing) miR-21 and probe CA-II inhibition-derived cell growth arrest. This proposal is innovative because it develops the first examples of activating protein inhibitors in response to miRs. Further, this project will provide impetus to shift general research into examining non- covalent mechanisms for prodrug activation. This work is significant because (a) it is a seminal step in a continuum of research aimed, in the long-term, at developing miR-21 triggered prodrugs, and (b) it will exert a sustained influence on the field of supramolecular chemistry by enhancing our understanding of how key principles of molecular recognition (such as host/guest interactions and multivalency) in combination with DNA assembly and structure-switching phenomena can be used to develop dynamic protein-binders. ) PUBLIC HEALTH RELEVANCE: This proposal is relevant to public health because fundamental studies on protein inhibitors that are triggered by oncogenic microRNA-21 has the potential to lead to prodrugs that selectively target cancer cells, thereby attenuating the systemic adverse effects and poor patient outcomes endemic to conventional chemotherapy. Thus, the proposed research is particularly relevant to the mission of the NIH that pertains to reducing the burden of illness. )
描述(由申请人提供):由癌症生物标志物触发的前药是有吸引力的,因为它们有可能在癌细胞中优先活化,从而减少与常规化疗相关的严重不良反应。虽然已经发现了许多癌症生物标志物,但由酶触发的前药一直是主要焦点,因为酶可以通过共价转化激活前药。因此,在使用非酶生物标志物进行前药活化中存在障碍,因为我们对如何开发选择性识别不能促进共价转化的生物标志物并被其活化的分子的理解不足。这种知识差距的存在阻碍了可以开发的前药的全部范围。因此,该项目的长期愿景是产生非共价触发的前药。这一基础科学应用的目的是建立microRNA-21(miR-21)(一种高度失调的致癌miR)非共价激活蛋白质抑制剂的基本超分子机制,这是实现我们长期目标的开创性一步。我们将通过两种互补的设计策略(分别为目的1和2)来测试本申请的中心假设,即miR-21诱导型蛋白拮抗剂可以通过开发DNA-小分子嵌合体(DC)来实现,所述DNA-小分子嵌合体在与miR-21特异性结合序列后经历从失活构象到活化状态的结构转换。该项目的具体目标是开发(目标1)通过宿主/客体相互作用失活的发夹形成DC和(目标2)通过与引导链形成双链体失活的双齿DC,作为临床相关碳酸酐酶-II(CA-II)的miR-21响应性抑制剂。在这两个目标中,我们将合成和表征各自的DC系统,并将通过许多光谱实验(包括紫外-可见和荧光淬灭)探测它们经历miR-21诱导的结构转换到激活状态的能力。随后,将评估失活和活性DC构象抑制CA-II的不同能力(通过比色酯酶测定)。在优化DC系统的结构(包括增强CA-II结合和核酸酶抗性)之后,我们将DC转染到过表达miR-21的细胞系(和表达不足的对照细胞系)中,并探测CA-II抑制衍生的细胞生长停滞。该提案具有创新性,因为它开发了响应miR的激活蛋白质抑制剂的第一个例子。此外,该项目将提供动力,将一般研究转移到检查前药活化的非共价机制。这项工作是重要的,因为(a)它是旨在长期开发miR-21触发的前药的连续研究中的开创性步骤,和(B)它将通过增强我们对分子识别的关键原理如何的理解而对超分子化学领域产生持续的影响结合DNA组装和结构转换现象,可以使用动态蛋白质结合剂(如主体/客体相互作用和多价性)来开发动态蛋白质结合剂。) 公共卫生相关性:这一提议与公共卫生有关,因为对致癌microRNA-21触发的蛋白质抑制剂的基础研究有可能导致选择性靶向癌细胞的前药,从而减轻常规化疗特有的全身不良反应和不良患者结局。因此,拟议中的研究与NIH的使命特别相关,即减轻疾病负担。)

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Janarthanan Jayawickramarajah其他文献

Janarthanan Jayawickramarajah的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Janarthanan Jayawickramarajah', 18)}}的其他基金

Acquisition of a Surface Plasmon Resonance Biosensor: Enhancing Biomedical (Bio)Molecular Recognition Projects
获得表面等离子共振生物传感器:增强生物医学(生物)分子识别项目
  • 批准号:
    8826435
  • 财政年份:
    2015
  • 资助金额:
    $ 28.6万
  • 项目类别:
Supramolecular Approaches to Protein Inhibitors Activated by MicroRNA-21
MicroRNA-21 激活蛋白质抑制剂的超分子方法
  • 批准号:
    8466335
  • 财政年份:
    2012
  • 资助金额:
    $ 28.6万
  • 项目类别:
Supramolecular Approaches to Protein Inhibitors Activated by MicroRNA-21
MicroRNA-21 激活蛋白质抑制剂的超分子方法
  • 批准号:
    8812883
  • 财政年份:
    2012
  • 资助金额:
    $ 28.6万
  • 项目类别:

相似海外基金

Unraveling Adverse Effects of Checkpoint Inhibitors Using iPSC-derived Cardiac Organoids
使用 iPSC 衍生的心脏类器官揭示检查点抑制剂的副作用
  • 批准号:
    10591918
  • 财政年份:
    2023
  • 资助金额:
    $ 28.6万
  • 项目类别:
Optimization of mRNA-LNP vaccine for attenuating adverse effects and analysis of mechanism behind adverse effects
mRNA-LNP疫苗减轻不良反应的优化及不良反应机制分析
  • 批准号:
    23K15383
  • 财政年份:
    2023
  • 资助金额:
    $ 28.6万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Elucidation of adverse effects of combined exposure to low-dose chemicals in the living environment on allergic diseases and attempts to reduce allergy
阐明生活环境中低剂量化学品联合暴露对过敏性疾病的不良影响并尝试减少过敏
  • 批准号:
    23H03556
  • 财政年份:
    2023
  • 资助金额:
    $ 28.6万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Green tea-based nano-enhancer as an adjuvant for amplified efficacy and reduced adverse effects in anti-angiogenic drug treatments
基于绿茶的纳米增强剂作为抗血管生成药物治疗中增强疗效并减少不良反应的佐剂
  • 批准号:
    23K17212
  • 财政年份:
    2023
  • 资助金额:
    $ 28.6万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Effects of Tobacco Heating System on the male reproductive function and towards to the reduce of the adverse effects.
烟草加热系统对男性生殖功能的影响以及减少不利影响。
  • 批准号:
    22H03519
  • 财政年份:
    2022
  • 资助金额:
    $ 28.6万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Mitigating the Adverse Effects of Ultrafines in Pressure Filtration of Oil Sands Tailings
减轻油砂尾矿压力过滤中超细粉的不利影响
  • 批准号:
    563657-2021
  • 财政年份:
    2022
  • 资助金额:
    $ 28.6万
  • 项目类别:
    Alliance Grants
1/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
1/4-破译ECT结果和不良反应的机制(DECODE)
  • 批准号:
    10521849
  • 财政年份:
    2022
  • 资助金额:
    $ 28.6万
  • 项目类别:
4/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
4/4-破译ECT结果和不良反应的机制(DECODE)
  • 批准号:
    10671022
  • 财政年份:
    2022
  • 资助金额:
    $ 28.6万
  • 项目类别:
2/4 Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
2/4 ECT 结果和不良反应的破译机制(DECODE)
  • 批准号:
    10670918
  • 财政年份:
    2022
  • 资助金额:
    $ 28.6万
  • 项目类别:
Downsides of downhill: The adverse effects of head vibration associated with downhill mountain biking on visuomotor and cognitive function
速降的缺点:与速降山地自行车相关的头部振动对视觉运动和认知功能的不利影响
  • 批准号:
    2706416
  • 财政年份:
    2022
  • 资助金额:
    $ 28.6万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了