Beauveriolide-Derived Cyclodepsipeptides as a New Class of Anti-Alzheimer's Drugs
Beauveriolide 衍生的环缩酚肽作为一类新型抗阿尔茨海默病药物
基本信息
- 批准号:7758245
- 负责人:
- 金额:$ 19.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-01-15 至 2010-12-31
- 项目状态:已结题
- 来源:
- 关键词:Acyl Coenzyme AAffectAlzheimer&aposs DiseaseAmericasAmino AcidsAmyloidAntibodiesAtherosclerosisBiologicalBiological AssayBiological FactorsBrainBrain regionC-terminalCell Culture TechniquesCell LineCellsChinese Hamster Ovary CellCholesterolCholesterol HomeostasisComplexComputer SimulationCost of IllnessCyclodepsipeptidesDementiaDevelopmentDiseaseEmotionalEnzyme-Linked Immunosorbent AssayEventExhibitsGenerationsGeneticGiftsGrantHumanImpaired cognitionIn VitroInvestigationLibrariesLife ExpectancyLipidsLiposomesMeasurementMeasuresMemory impairmentMethodsMicroscopyModificationMolecular ProbesMusNeuroblastomaNeuronsOralPeptidesPersonalityPharmaceutical PreparationsPhasePopulationProductionPropertyProteinsPublic HealthQuality of lifeRandomizedReportingScanningSideSolidSolutionsSpecific qualifier valueStagingStaining methodStainsSterol O-AcyltransferaseStructureSwitzerlandTestingTherapeuticVirtual LibraryWestern BlottingWorkbasecostdesigndrug discoveryin vivoinhibitor/antagonistmacrophagememberoil red Opreventpsychologicpublic health relevanceresponsesecretasesmall molecule librariessocial
项目摘要
DESCRIPTION (provided by applicant): The pathogenic event common to all forms of Alzheimer's disease (AD) is the abnormal accumulation of the amyloid 2-peptide (A2) in specific regions of the brain. This accumulation of A2 is considered a key pathological event in AD and is the basis of the so-called amyloid hypothesis of the disease. Therefore, therapeutic approaches that reduce the accumulation of A2 are currently being sought. It has been shown definitively that the generation and clearance of A2 in the CNS is regulated by cholesterol homeostasis. Compounds that perturb cellular free cholesterol homeostasis such as acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors have been shown both in vitro and in vivo to reduce A2 production and secretion. However, it is generally the case that ACAY inhibitors exhibit poor oral activity. The beauveriolides are a new class of fungal metabolites that have been shown to be orally active ACAT inhibitors that are currently being investigated as potential therapeutics for atherosclerosis. NB No studies have been reported to date on the investigation of the A2-inhibitory effect of the natural product beauveriolides or beauveriolide-inspired compounds. The hypothesis being tested in this R21 is that the natural product beauveriolides and libraries of beauveriolide-inspired compounds should reduce A2- production and secretion in vitro via inhibition of ACAT and perturbation of cholesterol homeostasis. They would in such a case be a NEW CLASS of potential AD therapeutics working via an established mechanism of action and hence this proposal is entirely within the remit of the PA-06-261 titled Grants for Alzheimer's Disease Drug Discovery (R21). We will investigate this hypothesis under the remit of the following two specific aims: Specific aim #1. Synthesis of beauveriolide-derived cyclodepsipeptide and cyclopeptide libraries In this specific aim libraries of beauveriolide-inspired structures are proposed (L1/L1', L2, L3 and L4). The key structural aspects being optimized are the macrolactone ring, the lipid side chain and the three hydrophobic amino acid components of the ring. Prior to selection for synthesis, all virtual library members will first be interrogated using in silico methods (the QikProp v3.0 suite of Maestro v 8.0) for favorable properties including Lipinkski's rule of 5, log BB and oral absorbtion. Only those members that fulfill the criterion will be synthesized. The synthesis is proposed to be a mixed solid- phase/solution phase approach. Library synthesis and optimization is proposed to occur in two stages, the first being randomization of the macrolactone and lipid side chain (libraries L1/L1') which will then be screened for biological activity as outlined in specific aim #2. The active compounds from L1/L1' will then be further refined through structural modifications of the hydrophobic amino-acids (libraries L2, L3 and L4) using positional scanning. Specific aim #2: To determine whether synthetic beauveriolide-inspired libraries reduce the levels of 2-secretase cleavage products of APP, including A2 in vitro In this specific aim there are three sub-aims each being a cell-culture assay designed to assess the ability of the library members synthesized in specific aim #1 to either 1. reduce lipid loading or 2. reduce A2 production and secretion. All analyses will be correlated with measurements of total protein production (BCA analysis) and free and esterified cholesterol (Amplex Red assay, Molecular Probes). Sub-aim 2.1 Measuring lipid loading in culture macrophages. Lipid droplet formation will be measured in a cultured murine macrophage cell line (J774.1) that has been treated with cholesterol-loaded liposomes. Quantification of lipid loading will be performed by microscopy of fixed and stained (H&E and oil-red O) cells. Sub-aim 2.2 ELISA assay to measure A2 secretion in cell-culture For this specific aim the CHO cell-lines stably transfected with human APP751 (7WD10 cell line and AC29, gifts from Prof. Ta-Yuan Chang) will be treated with library members from specific aim #1. The levels of A240 and A242 -secreted will be determined using a commercially-available ELISA kit (The Genetics Company, Switzerland). Sub-aim 2.3 Measurement of APP 2-cleavage product (2-APP-CTF) in cell culture In order to test the response of human neuronal cells to the chemical libraries synthesized in specific aim # 1 we will analyze the levels of 2-APP-CTF generated by the SH-SY5Y neuroblastoma cell line (ATCC, VA, US) using Western blot analysis with commercially available antibodies. These cells do not generate a detectable level of A2, but do generate detectable levels of 2-C-terminal fragments (2-APP-CTF), which have been analyzed in previous studies of ACAT inhibition and are indicative of 2-cleavage products in general, one of which is A2. NB CP-113,818 will be studied as a control ACAT inhibitor in this R21 proposal studies (gift from Pfizer Inc., c/o Mr.D. W. Owens, Pfizer Compound transfer manager). PUBLIC HEALTH RELEVANCE: Alzheimer's disease is now the most common form of dementia, affecting up to 15 million people worldwide. As a result of the increase in life expectancy, it is anticipated that by 2050 approximately 25 % of the world population will be over 65, of which one third are likely to develop AD. AD is a complex and genetically heterogeneous disease, characterized by progressive memory deficit, cognitive impairment and personality changes accompanied by specific structural abnormalities in the brain. In monetary terms, AD is already America's third most expensive disease - costing over $100 billion per year. Add to this the social, psychological and emotional costs of sufferers' and carers' diminishing quality of life and it becomes clear that inhibiting the development of Alzheimer's would have a hugely beneficial impact on public health and wealth. This project describes the development of a new class of compounds that may prevent and/or AD.
描述(由申请人提供):所有形式的阿尔茨海默病(AD)的共同致病事件是淀粉样蛋白2肽(A2)在大脑特定区域的异常积累。A2的积累被认为是AD的一个关键病理事件,也是该疾病所谓的淀粉样蛋白假说的基础。因此,目前正在寻求减少A2积累的治疗方法。研究明确表明,中枢神经系统中A2的生成和清除受胆固醇稳态调节。体外和体内实验均显示,干扰细胞游离胆固醇稳态的化合物,如酰基辅酶A:胆固醇酰基转移酶(ACAT)抑制剂,可减少A2的产生和分泌。然而,ACAY抑制剂通常表现出较差的口服活性。beauveriolides是一类新的真菌代谢物,已被证明是口服活性ACAT抑制剂,目前正在研究作为动脉粥样硬化的潜在治疗药物。注:迄今为止还没有关于天然产物beauveriolides或beauveriolides激发的化合物对a2抑制作用的研究报道。本研究验证的假设是,天然产物beauveroliides和beauveroliides激发的化合物库应该通过抑制ACAT和扰乱胆固醇稳态来减少体外A2-的产生和分泌。在这种情况下,它们将成为一类新的潜在的阿尔茨海默病治疗药物,通过既定的作用机制发挥作用,因此该提案完全在PA-06-261题为“阿尔茨海默病药物发现资助”(R21)的职权范围内。我们将在以下两个具体目标的范围内调查这个假设:具体目标#1。在这个特定的目标下,提出了beauveroliide衍生的环沉积肽和环肽文库(L1/L1', L2, L3和L4)。优化的关键结构方面是大内酯环、脂质侧链和环的三个疏水氨基酸组分。在选择合成之前,所有虚拟库成员将首先使用计算机方法(Maestro v 8.0的QikProp v3.0套件)进行询问,以获得有利的特性,包括Lipinkski的5法则,对数BB和口腔吸收。只有那些满足标准的成员才会被合成。建议采用固/固相混合合成方法。文库的合成和优化建议分两个阶段进行,第一个阶段是大内酯和脂质侧链(文库L1/L1’)的随机化,然后根据具体目标#2进行生物活性筛选。然后通过位置扫描对疏水氨基酸(L2、L3和L4文库)进行结构修饰,进一步提炼L1/L1'中的活性化合物。特定目标#2:确定合成的beauveroliide启发文库是否降低了APP 2-分泌酶切割产物的水平,包括体外A2。在这个特定目标中,有三个子目标,每个子目标都是一个细胞培养实验,旨在评估在特定目标#1中合成的文库成员的能力。减少脂质负荷或2。减少A2的产生和分泌所有分析将与总蛋白产量(BCA分析)和游离胆固醇和酯化胆固醇(Amplex Red测定,分子探针)的测量相关。亚目的2.1测定培养巨噬细胞的脂质负荷。脂滴形成将在培养的小鼠巨噬细胞细胞系(J774.1)中测量,该细胞系已被胆固醇负载脂质体处理。将通过显微镜对固定和染色(H&E和油红O)细胞进行脂质负载定量。为了达到这个特异性目的,稳定转染了人APP751的CHO细胞系(7WD10细胞系和AC29细胞系,由Chang Ta-Yuan教授赠送)将用特异性目标#1的库成员进行处理。A240和A242的分泌水平将使用市售ELISA试剂盒(The Genetics Company, Switzerland)进行测定。亚目标2.3细胞培养中APP 2-裂解产物(2-APP-CTF)的测量为了测试人类神经元细胞对特定目标1中合成的化学文库的反应,我们将使用市售抗体使用Western blot分析SH-SY5Y神经母细胞瘤细胞系(ATCC, VA, US)产生的2-APP-CTF的水平。这些细胞不会产生可检测水平的A2,但会产生可检测水平的2-c末端片段(2-APP-CTF),这些片段在之前的ACAT抑制研究中被分析过,通常是2-裂解产物的指示物,其中一个是A2。NB CP-113,818将作为对照ACAT抑制剂在这项R21提案研究中进行研究(辉瑞公司的礼物,c/o Mr.D。W. Owens,辉瑞化合物转移经理)。公共卫生相关性:阿尔茨海默病现在是最常见的痴呆症,影响全世界多达1500万人。由于预期寿命的延长,预计到2050年,世界上大约25%的人口将超过65岁,其中三分之一可能会患上阿尔茨海默病。AD是一种复杂的遗传异质性疾病,其特征是进行性记忆缺陷、认知障碍和人格改变,并伴有特定的大脑结构异常。从金钱角度来看,阿尔茨海默病已经是美国第三大最昂贵的疾病——每年花费超过1000亿美元。再加上患者和护理人员的生活质量下降所带来的社会、心理和情感成本,很明显,抑制阿尔茨海默氏症的发展将对公众健康和财富产生巨大的有益影响。本项目描述了一类新的化合物的开发,可以预防和/或AD。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The natural products beauveriolide I and III: a new class of beta-amyloid-lowering compounds.
- DOI:10.1002/cbic.200900139
- 发表时间:2009-05-25
- 期刊:
- 影响因子:3.2
- 作者:Witter, Daniel P.;Chen, Yanping;Rogel, Joseph K.;Boldt, Grant E.;Wentworth, Paul, Jr.
- 通讯作者:Wentworth, Paul, Jr.
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PAUL WENTWORTH其他文献
PAUL WENTWORTH的其他文献
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{{ truncateString('PAUL WENTWORTH', 18)}}的其他基金
C3 Tumor Associated Carbohydrate Antigen Bioconjugates
C3 肿瘤相关碳水化合物抗原生物缀合物
- 批准号:
8424948 - 财政年份:2012
- 资助金额:
$ 19.98万 - 项目类别:
C3 Tumor Associated Carbohydrate Antigen Bioconjugates
C3 肿瘤相关碳水化合物抗原生物缀合物
- 批准号:
8301502 - 财政年份:2012
- 资助金额:
$ 19.98万 - 项目类别:
C3 chemical conjugation to improve the anti-cocaine immune response
C3化学缀合改善抗可卡因免疫反应
- 批准号:
8233313 - 财政年份:2011
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$ 19.98万 - 项目类别:
C3 chemical conjugation to improve the anti-cocaine immune response
C3化学缀合改善抗可卡因免疫反应
- 批准号:
8092919 - 财政年份:2011
- 资助金额:
$ 19.98万 - 项目类别:
Lactobacilli surface antibody expression for in vivo protection against cholera
乳酸杆菌表面抗体表达可体内预防霍乱
- 批准号:
7772625 - 财政年份:2010
- 资助金额:
$ 19.98万 - 项目类别:
Lactobacilli surface antibody expression for in vivo protection against cholera
乳酸杆菌表面抗体表达可体内预防霍乱
- 批准号:
8033092 - 财政年份:2010
- 资助金额:
$ 19.98万 - 项目类别:
Antibody Generation of ROS and Macular Degeneration
ROS 和黄斑变性的抗体生成
- 批准号:
7273892 - 财政年份:2006
- 资助金额:
$ 19.98万 - 项目类别:
Investigating the link between the atheronals and aging
研究动脉粥样硬化与衰老之间的联系
- 批准号:
7124089 - 财政年份:2006
- 资助金额:
$ 19.98万 - 项目类别:
Investigating the link between the atheronals and aging
研究动脉粥样硬化与衰老之间的联系
- 批准号:
7273894 - 财政年份:2006
- 资助金额:
$ 19.98万 - 项目类别:
Antibody Generation of ROS and Macular Degeneration
ROS 和黄斑变性的抗体生成
- 批准号:
7096710 - 财政年份:2006
- 资助金额:
$ 19.98万 - 项目类别:
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