Development of Peptide-Conjugate Biomimics for Targeted Ti(IV)-Based Anticancer D
用于靶向 Ti(IV) 基抗癌 D 的肽缀合物仿生学的开发
基本信息
- 批准号:9326257
- 负责人:
- 金额:$ 34.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-01 至 2019-08-31
- 项目状态:已结题
- 来源:
- 关键词:A549AcidsAffinityAlcohol or Other Drugs useAntineoplastic AgentsAstrocytesBindingBinding ProteinsBiological AvailabilityBiologyBiomimeticsBreathingCancer cell lineCell DeathCellsChemistryDNA BindingDevelopmentDrug DesignDrug TargetingEndosomesEthylenediaminesFamilyFibroblastsFormulationGenerationsGoalsHumanIonsKineticsLigand BindingLigandsMalignant NeoplasmsMalignant neoplasm of brainMass Spectrum AnalysisMeasurementMediatingMetabolic PathwayMetal Binding SiteMetalsNatureNormal CellOxidesPeptide ReceptorPeptidesPharmaceutical PreparationsPhysiologicalPlatinumPropertyProteinsProtocols documentationSeriesSerum ProteinsSiteSpecificityStructureSubstance PSystemTFRC geneTestingTherapeuticTitaniumTransferrinWorkaqueousbasecancer cellcytotoxiccytotoxicitydesigndrug candidatedrug marketinnovationinsightlung Carcinomametabolomicsnoveloverexpressionpreferenceprotein aminoacid sequencepublic health relevancereceptorsmall moleculesynergism
项目摘要
DESCRIPTION (provided by applicant): Titanium(IV) compounds are excellent anticancer drug candidates with a broad spectrum of effect. Formulation issues due to the solution instability of these compounds and the generation of inert Ti(IV) oxide species have hindered their transition to the drug market. Several biomolecules, namely the serum protein transferrin (Tf), circumvent this problem by providing stable coordination sites that enable Ti(IV) to be transported in the body. The proposal herein seeks to exploit the Tf metal binding site and its intracellular metal transport in the development of a biomimetic drug design strategy for Ti(IV)-based anticancer compounds. Novel ligands will be synthesized specific to facilitating the anticancer properties of Ti(IV) by containing two important structural components. One component is a bioactive peptide to enable selective and receptor-mediated transport into cancer cells. The bioactive peptides substance P (SP) and transferrin receptor 1 binding peptides are excellent candidates for the peptide component of the Ti(IV) ligands because their primary receptors are overexpressed in many cancer cells relative to normal cells. These receptors are not overexpressed in the same cancer cell lines and thus this study will show how bioactive peptides can be used to fine-tune targeting of select cancers. The peptide component will be conjugated to a Tf mimicking metal binding moiety with a metal coordination preference that can be manipulated for Ti(IV) release in cancer cells. The N,N'-di(o-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid (HBED) and deferasirox metal binding ligands are suitable for this purpose. HBED binds Ti(IV) with a high affinity but binds Fe(III) with an even stronger affinity and the same is expected of deferasirox. The ligands have the potential to stably transport Ti(IV) into cells and then release Ti(IV) in exchange for Fe(III). By depleting cancer cells of Fe(III), which have a higher requirement for the metal ion, the ligands can work in synergism with Ti(IV) to trigger cell death. A series of cytotoxicity mechanistic studies of the Ti(IV) peptide-conjugate compounds will be performed to examine the contributions of the peptide, the metal binding moiety, and the Ti(IV) ion. The kinetics of Ti(IV) displacement by Fe(III) will be investigated to determine its physiological feasibility. Structure activity relatioship studies will be performed to elucidate the structural properties of both the peptide and metal binding moiety components that maximize the cytotoxicity of Ti(IV). In addition, insight into intracellular Ti(IV) target sites and metabolic pathways inhibited by Ti(IV) will be garnered through a combination of metallomics and metabolomics mass spectrometry studies. These mechanistic studies will afford optimization of the rationally designed Ti(IV) compounds.
描述(由申请人提供):钛(IV)化合物是具有广谱作用的优秀抗癌候选药物。由于这些化合物的溶液不稳定性和惰性Ti(IV)氧化物物种的产生而导致的配方问题阻碍了它们向药物市场的过渡。几种生物分子,即血清蛋白转铁蛋白(Tf),通过提供稳定的配位位点,使Ti(IV)在体内转运,从而避免了这个问题。本文的建议旨在利用Tf金属结合位点及其细胞内金属转运,开发基于Ti(IV)的抗癌化合物的仿生药物设计策略。将合成新的配体,通过包含两个重要的结构组分来促进Ti(IV)的抗癌特性。一种成分是生物活性肽,能够选择性地和受体介导地转运到癌细胞中。生物活性肽P物质(SP)和转铁蛋白受体1结合肽是Ti(IV)配体的肽组分的极好候选物,因为它们的主要受体相对于正常细胞在许多癌细胞中过表达。这些受体在相同的癌细胞系中不会过表达,因此这项研究将展示生物活性肽如何用于微调选定癌症的靶向。肽组分将与具有金属配位偏好的Tf模拟金属结合部分缀合,其可以被操纵用于癌细胞中的Ti(IV)释放。N,N '-二(邻羟基苄基)乙二胺-N,N'-二乙酸(HBED)和地拉罗司金属结合配体适用于此目的。HBED以高亲和力结合Ti(IV),但以甚至更强的亲和力结合Fe(III),预期地拉罗司也是如此。配体具有稳定地将Ti(IV)转运到细胞中,然后释放Ti(IV)以交换Fe(III)的潜力。通过消耗癌细胞的Fe(III)(其对金属离子具有更高的需求),配体可以与Ti(IV)协同作用以触发细胞死亡。将对Ti(IV)肽-缀合物化合物进行一系列细胞毒性机制研究,以检查肽、金属结合部分和Ti(IV)离子的贡献。将研究Fe(III)置换Ti(IV)的动力学,以确定其生理可行性。将进行结构活性相关性研究,以阐明使Ti(IV)细胞毒性最大化的肽和金属结合部分组分的结构特性。此外,通过金属组学和代谢组学质谱研究的结合,将深入了解细胞内Ti(IV)靶位点和Ti(IV)抑制的代谢途径。这些机制的研究将提供合理设计的Ti(IV)化合物的优化。
项目成果
期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Erratum to: Purification and characterization of a cytochrome c with novel caspase-3 activation activity from the pathogenic fungus Rhizopus arrhizus.
勘误:从病原真菌无根霉中纯化和鉴定具有新型 caspase-3 激活活性的细胞色素 c。
- DOI:10.1186/s12858-016-0059-8
- 发表时间:2016
- 期刊:
- 影响因子:0
- 作者:Saxena,Manoj;Sharma,RohitKumar;Ramirez-Paz,Josell;Tinoco,ArthurD;Griebenow,Kai
- 通讯作者:Griebenow,Kai
Inducing cell death in vitro in cancer cells by targeted delivery of cytochrome c via a transferrin conjugate.
- DOI:10.1371/journal.pone.0195542
- 发表时间:2018
- 期刊:
- 影响因子:3.7
- 作者:Saxena M;Delgado Y;Sharma RK;Sharma S;Guzmán SLPL;Tinoco AD;Griebenow K
- 通讯作者:Griebenow K
Exploring titanium(IV) chemical proximity to iron(III) to elucidate a function for Ti(IV) in the human body.
- DOI:10.1016/j.ccr.2018.03.006
- 发表时间:2018-05-15
- 期刊:
- 影响因子:20.6
- 作者:Saxena M;Loza-Rosas SA;Gaur K;Sharma S;Pérez Otero SC;Tinoco AD
- 通讯作者:Tinoco AD
Unusual Synergism of Transferrin and Citrate in the Regulation of Ti(IV) Speciation, Transport, and Toxicity.
- DOI:10.1021/jacs.6b01966
- 发表时间:2016-05-04
- 期刊:
- 影响因子:15
- 作者:Tinoco AD;Saxena M;Sharma S;Noinaj N;Delgado Y;Quiñones González EP;Conklin SE;Zambrana N;Loza-Rosas SA;Parks TB
- 通讯作者:Parks TB
Exploring the pH dependent aqueous speciation of metal complexes through UV-Vis spectroscopy.
通过紫外-可见光谱探索金属配合物的 pH 依赖性水相形态。
- DOI:10.1021/acs.jchemed.9b01199
- 发表时间:2020
- 期刊:
- 影响因子:3
- 作者:Gaur,Kavita;Cruz,YahairaM;SantiagoEspinoza,JoséA;MoralesRueda,CarlosA;Loza-Rosas,SergioA;Fernández-Vega,LaurenV;Benjamín-Rivera,JosuéA;Álvarez,Adelis;Tinoco,ArthurD
- 通讯作者:Tinoco,ArthurD
{{
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 }}
Arthur David Tinoco其他文献
Arthur David Tinoco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('Arthur David Tinoco', 18)}}的其他基金
Fusing the commercial drugs triapine and deferasirox to create Ti(IV) anticancer compounds that inhibit the bioavailability of iron
将商业药物三甲平和地拉罗司融合,产生 Ti(IV) 抗癌化合物,抑制铁的生物利用度
- 批准号:
10043908 - 财政年份:2020
- 资助金额:
$ 34.8万 - 项目类别:
Development of Peptide-Conjugate Biomimics for Targeted Ti(IV)-Based Anticancer D
用于靶向 Ti(IV) 基抗癌 D 的肽缀合物仿生学的开发
- 批准号:
8667206 - 财政年份:2014
- 资助金额:
$ 34.8万 - 项目类别:
相似国自然基金
具有抗癌活性的天然产物金霉酸(Aureolic acids)全合成与选择性构建2-脱氧糖苷键
- 批准号:22007039
- 批准年份:2020
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
海洋放线菌来源聚酮类化合物Pteridic acids生物合成机制研究
- 批准号:
- 批准年份:2019
- 资助金额:10.0 万元
- 项目类别:省市级项目
手性Lewis Acids催化的分子内串联1,5-氢迁移/环合反应及其在构建结构多样性手性含氮杂环化合物中的应用
- 批准号:21372217
- 批准年份:2013
- 资助金额:80.0 万元
- 项目类别:面上项目
对空气稳定的新型的有机金属Lewis Acids催化剂制备、表征与应用研究
- 批准号:21172061
- 批准年份:2011
- 资助金额:30.0 万元
- 项目类别:面上项目
钛及含钛Lewis acids促臭氧/过氧化氢体系氧化性能的广普性、高效性及其机制
- 批准号:21176225
- 批准年份:2011
- 资助金额:60.0 万元
- 项目类别:面上项目
基于Zip Nucleic Acids引物对高度降解和低拷贝DNA检材的STR分型研究
- 批准号:81072511
- 批准年份:2010
- 资助金额:31.0 万元
- 项目类别:面上项目
海洋天然产物Makaluvic acids 的全合成及其对南海鱼虱存活的影响
- 批准号:30660215
- 批准年份:2006
- 资助金额:21.0 万元
- 项目类别:地区科学基金项目
相似海外基金
Lipid nanoparticle-mediated Inhalation delivery of anti-viral nucleic acids
脂质纳米颗粒介导的抗病毒核酸的吸入递送
- 批准号:
502577 - 财政年份:2024
- 资助金额:
$ 34.8万 - 项目类别:
CAREER: Highly Rapid and Sensitive Nanomechanoelectrical Detection of Nucleic Acids
职业:高度快速、灵敏的核酸纳米机电检测
- 批准号:
2338857 - 财政年份:2024
- 资助金额:
$ 34.8万 - 项目类别:
Continuing Grant
Double Incorporation of Non-Canonical Amino Acids in an Animal and its Application for Precise and Independent Optical Control of Two Target Genes
动物体内非规范氨基酸的双重掺入及其在两个靶基因精确独立光学控制中的应用
- 批准号:
BB/Y006380/1 - 财政年份:2024
- 资助金额:
$ 34.8万 - 项目类别:
Research Grant
Quantifying L-amino acids in Ryugu to constrain the source of L-amino acids in life on Earth
量化 Ryugu 中的 L-氨基酸以限制地球生命中 L-氨基酸的来源
- 批准号:
24K17112 - 财政年份:2024
- 资助金额:
$ 34.8万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Synthetic analogues based on metabolites of omega-3 fatty acids protect mitochondria in aging hearts
基于 omega-3 脂肪酸代谢物的合成类似物可保护衰老心脏中的线粒体
- 批准号:
477891 - 财政年份:2023
- 资助金额:
$ 34.8万 - 项目类别:
Operating Grants
Metabolomic profiles of responders and non-responders to an omega-3 fatty acids supplementation.
对 omega-3 脂肪酸补充剂有反应和无反应者的代谢组学特征。
- 批准号:
495594 - 财政年份:2023
- 资助金额:
$ 34.8万 - 项目类别:
Molecular recognition and enantioselective reaction of amino acids
氨基酸的分子识别和对映选择性反应
- 批准号:
23K04668 - 财政年份:2023
- 资助金额:
$ 34.8万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Integrated understanding and manipulation of hypoxic cellular functions by artificial nucleic acids with hypoxia-accumulating properties
具有缺氧累积特性的人工核酸对缺氧细胞功能的综合理解和操纵
- 批准号:
23H02086 - 财政年份:2023
- 资助金额:
$ 34.8万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Basic research toward therapeutic strategies for stress-induced chronic pain with non-natural amino acids
非天然氨基酸治疗应激性慢性疼痛策略的基础研究
- 批准号:
23K06918 - 财政年份:2023
- 资助金额:
$ 34.8万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Molecular mechanisms how arrestins that modulate localization of glucose transporters are phosphorylated in response to amino acids
调节葡萄糖转运蛋白定位的抑制蛋白如何响应氨基酸而被磷酸化的分子机制
- 批准号:
23K05758 - 财政年份:2023
- 资助金额:
$ 34.8万 - 项目类别:
Grant-in-Aid for Scientific Research (C)