Drug-like small molecule modulators of the Integrated Stress Response

综合应激反应的类药物小分子调节剂

• 批准号: 7458067
• 负责人: DAVID RON
• 金额: $ 33.05万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-20 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7458067
• 关键词: Active Sites; Affect; Aging; Allosteric Site; Amino Acids; Antibodies; Antibody Formation; Apical; Arts; Binding; Biochemical Process; Biological Assay; Biological Availability; Biological Response Modifier Therapy; Catalytic Domain; Cell Survival; Cells; Cessation of life; Client; Complex; Computing Methodologies; Condition; Cultured Cells; Data; Diabetes Mellitus; Disease; Docking; Endoplasmic Reticulum; Environment; Enzymatic Biochemistry; Enzymes; Equilibrium; Event; Exhibits; Failure; Fluorescence Resonance Energy Transfer; Functional disorder; Future; Genetic; Glucokinase; Glycogen storage disease type II; Goals; Homeostasis; Human; In Vitro; Knock-out; Lead; Ligands; Lysosomal Storage Diseases; Lysosomes; Mediating; Modeling; Molecular Chaperones; Molecular Weight; Neurodegenerative Disorders; Numbers; Organ; Organelles; Organic Chemistry; PERK kinase; Parkinson Disease; Pathway interactions; Peptide Initiation Factors; Pharmaceutical Preparations; Pharmacy (field); Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physicians; Production; Protein Biosynthesis; Protein Dephosphorylation; Proteins; Quality Control; Recombinant Proteins; Recruitment Activity; Relaxation; Research Personnel; Role; Serine; Signal Transduction; Signal Transduction Pathway; Site; Sorting - Cell Movement; Specificity; Starvation; Stereotyping; Stream; Stress; Surface; System; Testing; Therapeutic; Upper arm; Virtual Library; antibody conjugate; attenuation; base; biological adaptation to stress; cell type; clinically relevant; coping; cost; desire; disease-causing mutation; enzyme replacement therapy; gene function; high throughput screening; human disease; improved; in vitro Assay; inhibitor/antagonist; loss of function; mutant; phosphatase inhibitor; programs; protein folding; protein misfolding; response; small molecule; success; tool; trafficking

DESCRIPTION (provided by applicant): Protein misfolding in the early secretory pathway exerts it pathological affects by two distinct mechanisms: Retention and degradation of misfolded mutant proteins by the endoplasmic reticulum's (ER) quality control machinery leads to loss-of-function phenotypes (exemplified by lysosomal storage diseases). Production and accumulation of the misfolded protein threatens the integrity of the organelle by causing ER stress, leading to cell dysfunction and death, which is believed to contribute to neurodegenerative disorders, diabetes mellitus and other diseases of aging. The protein folding environment in the ER is controlled by a small number of signal transduction pathways and these respond to ER stress in a stereotyped fashion, mediating the unfolded protein response (UPR). Recent evidence suggests that the level of signaling in the UPR is defined by global parameters and by the averaged needs of the ER's diverse protein clientele. It is unlikely therefore that the UPR is finely tuned to the specific exigencies of any one mutation-causing disease. Evidence for this has recently presented itself as circumstances in which knockout of normal genes that function in the UPR improved survival under conditions of ER stress. Such examples of failure of homeostasis indicate that the UPR can be manipulated therapeutically in pathophysiological conditions. Regulated phosphorylation and dephosphorylation of translation initiation factor 2a (elF2a) is a well understood and potentially malleable arm of the UPR, referred to as the integrated stress response (ISR). We propose to identify drug like small molecules that will enhance and others that will reduce the ISR's activity. Transient inhibition of the ISR might overwhelm the quality control mechanism of the ER and promote trafficking of enzymatically active mutant proteins to their functional compartment, alleviating the associated loss of function phenotypes. ISR inactivation might also prove beneficial in the cell culture based production of biotherapeutics used to treat diseases caused by misfolding by enzyme replacement therapy. Activators of the ISR are likely to protect cells and organs against the lethal consequences of ER stress and may prove useful in treating diseases of aging. To accomplish these goals we will develop high throughput screens (HTS) for compounds that inhibit the ER stress inducible elF2a kinase PERK and secondary screens to evaluate the potency, specificity, bioavailability and off-target effects of the compounds. In a parallel strand we will develop HTS assays for inhibitors of elF2a dephosphorylation and others for activators of elF2a kinases, which function by non-canonical mechanisms and activate the ISR without causing stress. The long-term goal of this proposal is therefore to create a pharmacological platform for manipulating the cellular response to misfolded proteins. Given the pervasive role of protein misfolding in human diseases, such agents are likely to become part of the therapeutic armamentarium of future physicians.

描述（由申请人提供）：早期分泌途径中的蛋白质错误折叠通过两种不同的机制施加其病理影响：内质网（ER）质量控制机制对错误折叠突变蛋白的保留和降解导致功能丧失表型（例如溶酶体贮积病）。错误折叠蛋白的产生和积累通过引起内质网应激威胁细胞器的完整性，导致细胞功能障碍和死亡，这被认为是导致神经退行性疾病、糖尿病和其他衰老疾病的原因。内质网中的蛋白质折叠环境由少数信号转导途径控制，这些信号转导途径以刻板的方式响应内质网应激，介导未折叠蛋白反应（UPR）。最近的证据表明，普遍定期审议中的信号水平是由全局参数和内质网不同蛋白质客户的平均需求决定的。因此，普遍定期审议不太可能精确地调整到任何一种引起突变的疾病的特定紧急情况。最近有证据表明，敲除在UPR中起作用的正常基因可改善内质网应激条件下的存活率。这些体内平衡失败的例子表明，在病理生理条件下，UPR可以被治疗性地操纵。翻译起始因子2a （elF2a）的磷酸化和去磷酸化调控是UPR的一个很好的理解和潜在的可塑性分支，被称为综合应激反应（ISR）。我们建议确定像小分子这样的药物会增强ISR的活性，而其他药物会降低ISR的活性。对ISR的短暂抑制可能会破坏内质网的质量控制机制，促进酶活性突变蛋白向其功能区转运，从而减轻相关的功能表型损失。ISR失活也可能在基于细胞培养的生物疗法生产中被证明是有益的，这些生物疗法用于治疗酶替代疗法引起的错误折叠疾病。ISR的激活剂可能保护细胞和器官免受内质网应激的致命后果，并可能被证明对治疗衰老疾病有用。为了实现这些目标，我们将开发高通量筛选（HTS）来抑制内质网应激诱导的elF2a激酶PERK，并进行二次筛选来评估这些化合物的效力、特异性、生物利用度和脱靶效应。在平行链中，我们将开发elF2a去磷酸化抑制剂和其他elF2a激酶激活剂的HTS分析，这些激活剂通过非规范机制起作用，激活ISR而不会引起应激。因此，这项提议的长期目标是创建一个药理学平台来操纵细胞对错误折叠蛋白质的反应。鉴于蛋白质错误折叠在人类疾病中的普遍作用，这些药物很可能成为未来医生治疗设备的一部分。