Tuning aminoglycosides for treatment of genetic diseases

调整氨基糖苷类药物治疗遗传病

基本信息

  • 批准号:
    8450640
  • 负责人:
  • 金额:
    $ 33.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-04-01 至 2015-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): A large number of human genetic diseases result from mutations that cause premature termination of the synthesis of proteins encoded by mutant genes. Currently, hundreds of such nonsense mutations are known, and several where shown to account for certain cases of fatal diseases, including cystic fibrosis (CF), Duchenne muscular dystrophy (DMD), Tay-Sachs, and more. For many of those diseases there is presently no effective treatment. In the last several years, it was shown that some aminoglycoside antibiotics (including gentamicin) have the ability to allow the mammalian ribosome to selectively read past a false-stop signal, but not a normal termination signal, and generate full-length functional proteins. However, high toxicity of these drugs in humans limits their therapeutic use. The main objective of this research is to develop novel aminoglycosides that will have efficient termination suppression activity, and at the same time will have reduced toxicity against mammalian cells. To date, the clinical application of aminoglycosides is limited to their use as antibacterial drugs, and no efforts have been made to optimize their activity as stop codon read-through inducers. Toward these ends, a collaborative effort is under way between several different laboratories and combines expertise of number of complementary disciplines to synthesize and elucidate the structure-activity- toxicity relationships of the designed drugs. The hypothesis behind the proposal is to separate the elements of the aminoglycosides structures that cause toxicity from those that are required for inducing nonsense suppression: designed structures exhibiting extensive specificity and selectivity for the cytoplasmic rRNA A site can decrease the functional dosing ranges and subsequently decrease the anticipated toxicity, including deleterious effects on mitochondrial protein synthesis machinery, making them potential drugs for the treatments of human genetic disorders. Our hypothesis is based on a series of recent observations in which we have shown that by reducing the specificity to prokaryotic ribosome and as such wiping away from aminoglycosides their "natural" antibacterial activity we reduce their action on eukaryotic mitochondrial protein synthesis machinery and as such significantly reduce their toxic effects on humans. Substantial therapeutic and economic benefits are anticipated from this study. The designed structures presented here are simple for preparation and the preliminary tests already discovered some variants with lower toxicity and greater read-through efficacy to restore functional CFTR protein from the mutant gene both in vitro and in vivo, including models closely predictive of results with human CF subjects, than those of gentamicin. Fulfillment of the goals of this project will provide the necessary knowledge and tools for uncovering new structures, which may act as novel drugs.
描述(由申请人提供):大量人类遗传性疾病是由突变引起的,这些突变导致突变基因编码的蛋白质合成提前终止。目前,已知有数百种这样的无义突变,其中几种被证明是某些致命疾病的原因,包括囊性纤维化(CF),杜氏肌营养不良症(DMD),泰-萨克斯等。对于其中许多疾病,目前没有有效的治疗方法。在过去的几年中,研究表明,一些氨基糖苷类抗生素(包括庆大霉素)具有允许哺乳动物核糖体选择性读取假终止信号而不是正常终止信号的能力,并产生全长功能蛋白。然而,这些药物在人体中的高毒性限制了它们的治疗用途。本研究的主要目的是开发新的氨基糖苷类,将具有有效的终止抑制活性,并在同一时间将有减少对哺乳动物细胞的毒性。迄今为止,氨基糖苷类的临床应用仅限于其作为抗菌药物的用途,并且没有努力优化其作为终止密码子通读诱导剂的活性。为了实现这些目标,几个不同的实验室之间正在进行合作,并结合了一些互补学科的专业知识,以合成和阐明所设计药物的结构-活性-毒性关系。该提议背后的假设是将引起毒性的氨基糖苷类结构的元素与诱导无义抑制所需的元素分开:对细胞质rRNA A位点表现出广泛特异性和选择性的设计结构可以降低功能剂量范围并随后降低预期的毒性,包括对线粒体蛋白质合成机制的有害作用,使它们成为治疗人类遗传疾病的潜在药物。我们的假设是基于一系列最近的观察,其中我们已经表明,通过降低对原核核糖体的特异性,从而消除氨基糖苷类的“天然”抗菌活性,我们减少了它们对真核线粒体蛋白质合成机制的作用,从而显著降低了它们对人类的毒性作用。预计本研究将带来实质性的治疗和经济效益。这里提出的设计结构易于制备,并且初步测试已经发现了一些具有较低毒性和更大通读效力的变体,以在体外和体内从突变基因恢复功能性CFTR蛋白,包括与庆大霉素相比,与人类CF受试者密切预测结果的模型。该项目目标的实现将为发现可能作为新药的新结构提供必要的知识和工具。

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 }}

Timor Baasov其他文献

Timor Baasov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('Timor Baasov', 18)}}的其他基金

Tuning aminoglycosides for treatment of genetic diseases
调整氨基糖苷类药物治疗遗传病
  • 批准号:
    8247665
  • 财政年份:
    2011
  • 资助金额:
    $ 33.13万
  • 项目类别:
Tuning aminoglycosides for treatment of genetic diseases
调整氨基糖苷类药物治疗遗传病
  • 批准号:
    8107761
  • 财政年份:
    2011
  • 资助金额:
    $ 33.13万
  • 项目类别:
Tuning aminoglycosides for treatment of genetic diseases
调整氨基糖苷类药物治疗遗传性疾病
  • 批准号:
    8636483
  • 财政年份:
    2011
  • 资助金额:
    $ 33.13万
  • 项目类别:

相似海外基金

Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
  • 批准号:
    MR/X02329X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.13万
  • 项目类别:
    Fellowship
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
  • 批准号:
    MR/Y009568/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.13万
  • 项目类别:
    Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
  • 批准号:
    10090332
  • 财政年份:
    2024
  • 资助金额:
    $ 33.13万
  • 项目类别:
    Collaborative R&D
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
  • 批准号:
    MR/X021882/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.13万
  • 项目类别:
    Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
  • 批准号:
    2312694
  • 财政年份:
    2024
  • 资助金额:
    $ 33.13万
  • 项目类别:
    Standard Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
  • 批准号:
    EP/Y003527/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.13万
  • 项目类别:
    Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
  • 批准号:
    EP/Y030338/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.13万
  • 项目类别:
    Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
  • 批准号:
    MR/X029557/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.13万
  • 项目类别:
    Research Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
  • 批准号:
    24K19395
  • 财政年份:
    2024
  • 资助金额:
    $ 33.13万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Collaborative Research: Changes and Impact of Right Ventricle Viscoelasticity Under Acute Stress and Chronic Pulmonary Hypertension
合作研究:急性应激和慢性肺动脉高压下右心室粘弹性的变化和影响
  • 批准号:
    2244994
  • 财政年份:
    2023
  • 资助金额:
    $ 33.13万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了