Probing the Proteinopathy Component of Light Chain Amyloidosis Pharmacologically
从药理学角度探讨轻链淀粉样变性的蛋白病成分
基本信息
- 批准号:10625486
- 负责人:
- 金额:$ 45.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AlbuminsAmericanAmino AcidsAmyloidosisAnilineBindingBinding SitesBiological AssayBuffersCardiacCell secretionChemistryChemotherapy-Oncologic ProcedureChromatographyClinical TrialsClonal ExpansionComputer softwareCoumarinsCoupledDataDegenerative DisorderDeteriorationDiagnosisDissociationDisulfidesDockingEndopeptidase KFamilyFluorescence PolarizationHumanKineticsLabelLeadLearningLengthLightLight-Chain ImmunoglobulinsLinkMalignant NeoplasmsMedicalMetabolicMolecular ConformationMultiple MyelomaOrganPathologyPatientsPeptide HydrolasesPharmaceutical ChemistryPharmaceutical PreparationsPlasmaPlasma CellsPlasma ProteinsPopulationPositioning AttributeProcessPublishingStructureStructure-Activity RelationshipTherapeuticTimeVariantX-Ray Crystallographyanalogbasecancer cellcomputerized toolsdesigndimerdrug candidateexperimental studyimprovedlead candidatemolecular sequence databasemonomerpharmacologicpreservationpreventprimary amyloidosis of light chain typescaffoldscreeningsmall moleculestandard of care
项目摘要
Project Summary
Immunoglobulin light chain amyloidosis (AL) is a degenerative disease that putatively arises from light chain
(LC) misfolding and aggregation. Full-length (FL) LCs are secreted from a clonally expanded plasma cell
population in AL. Thus, AL patients suffer from both a plasma cell cancer and a LC misfolding and
aggregation-associated proteinopathy that appears to compromise organ function, leading to progressive
organ deterioration. Currently, AL is treated by repurposed multiple myeloma drugs that kill the clonal plasma
cells secreting FL LCs. Mechanistically distinct therapeutic approaches are needed, particularly for patients
with cardiac involvement who cannot tolerate the currently available chemotherapy regimens. In this proposal,
we seek to produce lead candidates that ultimately would enable a clinical trial on a FL LC kinetic stabilizer
targeting the proteinopathy component of AL. In Specific Aim 1, we hypothesize that the LC kinetic stabilizers
to be synthesized in our hit-to-lead medicinal chemistry efforts can be dissected into four substructures—the
“anchor substructure”, the “aromatic core”, the “linker module” and the “terminal aromatic component”. This
hypothesis is based on 11 (FL LC)2•kinetic stabilizer crystal structures solved to date as well as the structure-
activity relationship data resulting from the synthesis of over 300 FL LC2 kinetic stabilizers during the past 18
months. We will continue to use structure-based design principles that we learned developing the drug
tafamidis, in addition to computational tools, especially the Schrödinger LiveDesign software, to replace the
metabolically unstable and potentially toxic coumarin aromatic core and the diethyl aniline anchor substructure
in our LC kinetic stabilizers, while introducing functionality to reduce albumin binding. The LiveDesign software
utilizes a weighted combination of the predicted LogP values and docking scores to accurately predict albumin
binding. In Specific Aim 2, we will develop FL LC2 plasma binding selectivity assays to validate our
computational efforts to diminish albumin binding. First, we will add fluorescently labeled FL amyloidogenic
LCs to pooled healthy donor plasma, along with proteinase K and a candidate kinetic stabilizer, and follow
proteinase K endoproteolysis linked to FL LC2 conformational excursions chromatographically over time. If the
kinetic stabilizer candidate selectively binds the amyloidogenic FL LC2 over all the other plasma proteins,
including albumin, FL LC2 proteinase K endoproteolysis will be prevented–this assay is largely developed.
Next, a subunit exchange assay will be developed to quantify pharmacologic FL LC2 kinetic stabilization in
human plasma. This assay also quantifies kinetic stabilizer binding to albumin. A fluorescently labeled
Cys214Ser FL LC2 variant facilitates subunit exchange experiments that afford the KD of kinetic stabilizer
binding to the FL LC2 variants added to healthy plasma, as well as the kinetic stabilizer KD for binding to
endogenous human albumin in plasma. These KDs will be used to generate binding selectivity ratios, i.e., KD of
kinetic stabilizer binding to albumin / KD of kinetic stabilizer binding to the FL LC2, which we will maximize.
项目摘要
免疫球蛋白轻链淀粉样变性(AL)是一种退化性疾病,推测是由轻链引起的
(LC)错误折叠和聚合。全长(FL)LCS从克隆膨胀的浆细胞分泌
人口这是Al患者患有浆细胞癌和LC折叠和疾病的患者
聚集相关的蛋白质病似乎会损害器官功能,导致渐进性
器官定义。目前,Al通过重新利用的多种骨髓瘤药物进行治疗,这些药物杀死克隆血浆
分泌FL LCS的细胞。需要机械上不同的治疗方法,特别是对于患者
由于心脏参与无法忍受当前可用的化学疗法方案。在此提案中,
我们寻求生产候选人,最终将在FL LC动力学稳定剂上进行临床试验
靶向Al的蛋白质病成分。在特定目标1中,我们假设LC动力学稳定器
在我们的命中至铅的药物化学工作中合成的综合,可以分为四个子结构 -
“锚亚结构”,“芳族核心”,“链接器模块”和“终端芳香族组件”。这
假设基于11(FL LC)2•迄今为止解决的动力学稳定器晶体结构以及结构 -
在过去的18个
月份。我们将继续使用基于结构的设计原理,我们学会了开发该药物
塔法米迪(Tafamidis
代谢不稳定且潜在的有毒香豆素芳香核和二乙基苯胺锚定下结构
在我们的LC动力学稳定器中,同时引入功能以减少白蛋白结合。 LiveSign软件
利用预测的LOGP值和对接分数的加权组合来准确预测专辑
结合。在特定目标2中,我们将开发FL LC2等离子体结合选择性测定以验证我们
计算努力减少白蛋白结合。首先,我们将添加荧光标记的FL淀粉样蛋白生成
LCS与蛋白酶K和候选动力学稳定剂一起汇总健康的供体等离子体,然后遵循
蛋白酶K内蛋白解体与FL LC2构象偏移在色谱上随着时间的流逝而连接。如果是
动力学稳定器候选者在所有其他血浆蛋白上选择性地结合淀粉样蛋白生成的FL LC2,
包括专辑,FL LC2蛋白酶K内蛋白溶解将被预防 - 该测定在很大程度上开发。
接下来,将开发一个亚基交换测定,以量化药物学FL LC2动力学稳定
人血浆。该测定还量化了动力学稳定器与专辑的结合。荧光标记
CYS214SER FL LC2变体收藏夹亚基交换实验,可提供动力学稳定器的KD
与添加到健康等离子体的FL LC2变体以及动力学稳定器KD结合以结合到与FL LC2的结合
血浆中的内源性人白蛋白。这些KD将用于产生结合选择比,即
动力学稳定器与动力学稳定器的专辑 / KD结合与FL LC2结合,我们将最大化。
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)
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JEFFERY W KELLY其他文献
JEFFERY W KELLY的其他文献
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{{ truncateString('JEFFERY W KELLY', 18)}}的其他基金
Probing the Proteinopathy Component of Light Chain Amyloidosis Pharmacologically
从药理学角度探讨轻链淀粉样变性的蛋白病成分
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Probing the Proteinopathy Component of Light Chain Amyloidosis Pharmacologically
从药理学角度探讨轻链淀粉样变性的蛋白病成分
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10186362 - 财政年份:2021
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