Engineering selective inhibition of metalloproteinases by tissue inhibitors of metalloproteinases (R01 GM132100 RESUB - *TIMPs)
通过金属蛋白酶组织抑制剂对金属蛋白酶进行工程选择性抑制(R01 GM132100 RESUB - *TIMP)
基本信息
- 批准号:10545017
- 负责人:
- 金额:$ 31.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAffinityArthritisAutoimmune DiseasesBindingBiological AssayBiological ModelsBiologyC-terminalCardiovascular DiseasesCatalytic DomainComplementComplexComputer AnalysisComputer ModelsCrotalus adamanteus proteinase IIDataDegenerative DisorderDevelopmentDirected Molecular EvolutionDiscriminationDiseaseDisease modelDiversity LibraryDose LimitingDrug TargetingEndopeptidasesEngineeringEnzymesEpitopesFamilyFoundationsFree EnergyGenerationsGoalsIndividualInflammatoryInhibition of Matrix Metalloproteinases PathwayKineticsLengthLibrariesMalignant NeoplasmsMapsMatrix Metalloproteinase InhibitorMatrix MetalloproteinasesMediatingMetalloproteasesMethodologyMethodsModelingMolecularMolecular ProbesMorphogenesisMusculoskeletalMutagenesisMutationN-terminalOutcomePathologicPathologyPeptide HydrolasesPharmaceutical PreparationsPhysiologicalPlayProcessProgression-Free SurvivalsProtease InhibitorProtein DynamicsProtein EngineeringProteinsPublishingReagentResearchRoleScaffolding ProteinShapesSpecificityStructural ModelsStructureSurfaceTherapeuticTissue EngineeringTissue Inhibitor of Metalloproteinase-1Tissue Inhibitor of MetalloproteinasesTissuesToxic effectVariantWorkX-Ray CrystallographyYeastsZincdesignearly phase clinical trialinhibitormolecular dynamicsmolecular recognitionnext generationnovelprotein complexprotein foldingscaffoldscreeningsynergismtherapeutic proteintherapeutic targettherapeutically effectivetool
项目摘要
PROJECT SUMMARY/ABSTRACT
Matrix metalloproteinases (MMPs) have long been regarded as promising therapeutic targets, but clinical trials
of early-generation MMP inhibitors in arthritis and cancer proved disappointing. Broad-spectrum MMP
inhibitors produced serious dose-limiting musculoskeletal toxicity and failed to extend progression-free survival
in cancer trials, partly due to the inability of the inhibitors to distinguish among different MMPs. This was a
critical problem, because some MMPs serve a primarily protective function, and it is now clear that
indiscriminate inhibition of all MMPs inevitably leads to poorer outcomes. Based on our published and
preliminary data, we hypothesize that tissue inhibitors of metalloproteinases (TIMPs), endogenous regulators
of the MMP family, can be engineered into highly selective MMP inhibitors free of undesired off-target
activities, to produce probes and therapeutics targeting individual MMPs with exquisite selectivity. In this
application, we will (a) optimize novel methodology for directed evolution of selective binders to discriminate
within the large families of related MMPs and adamalysin proteases, (b) uncover mechanisms of molecular
recognition that govern MMP-TIMP binding specificity, and (c) develop a toolbox of engineered TIMPs that
selectively target individual MMPs with highly enhanced specificity. To accomplish these goals, we will use
state-of-the-art directed evolution approaches to engineer the TIMP-1 scaffold for fine discrimination between
closely similar MMPs, reengineering N- and C-terminal TIMP domain epitopes and exploiting cooperativity
between domains. Additionally, we will integrate X-ray crystallographic and computational approaches to
elucidate the protein structural and dynamic features that govern affinity and selectivity of TIMP/MMP
complexes. This project will thus elucidate fundamental principles of molecular recognition governing
TIMP/MMP selectivity, and will produce designer TIMPs targeting single MMPs with highly enhanced
specificity, with potential for development as useful molecular probes and as protein therapeutics for the many
diseases driven by MMP dysregulation.
项目摘要/摘要
基质金属蛋白酶(MMPs)长期以来一直被认为是有希望的治疗靶点,但临床试验
治疗关节炎和癌症的早期一代基质金属蛋白酶抑制剂的研究结果令人失望。广谱基质金属蛋白酶
抑制剂产生严重的剂量限制的肌肉骨骼毒性,并未能延长无进展生存期
在癌症试验中,部分原因是抑制剂无法区分不同的MMP。这是一次
关键问题,因为一些MMP主要起到保护作用,现在很明显
不分青红皂白地抑制所有MMP不可避免地会导致更糟糕的结果。基于我们发布的和
初步数据,我们假设金属蛋白酶组织抑制物(TIMPs),内源性调节因子
作为基质金属蛋白酶家族的一员,可以被改造成高度选择性的基质金属蛋白酶抑制剂,而不会出现不受欢迎的脱靶现象
活性,生产针对单个MMPs的探针和疗法,具有精致的选择性。在这
应用,我们将(A)优化选择性结合物定向进化的新方法,以区分
在相关的MMPs和Adamalysin蛋白的大家族中,(B)揭示分子机制
管理MMP-TIMP结合特异性的识别,以及(C)开发一个工程TIMP工具箱,该工具箱
选择性地针对单个MMPs,具有高度增强的特异性。为了实现这些目标,我们将使用
最先进的定向进化方法来设计TIMP-1支架,以精细区分
相似的MMPs,N-端和C-端TIMP结构域表位的重组和协同作用
在域之间。此外,我们将整合X射线结晶学和计算方法,以
阐明控制TIMP/MMPs亲和力和选择性的蛋白质结构和动力学特征
复合体。因此,本项目将阐明分子识别的基本原理
TIMP/MMP选择性,并将生产针对单个MMP的设计型TIMP,具有高度增强的功能
特异性,具有作为有用的分子探针和许多蛋白质疗法的潜力
由基质金属蛋白酶失调引起的疾病。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Climbing Up and Down Binding Landscapes through Deep Mutational Scanning of Three Homologous Protein-Protein Complexes.
- DOI:10.1021/jacs.1c08707
- 发表时间:2021-10-20
- 期刊:
- 影响因子:15
- 作者:Heyne M;Shirian J;Cohen I;Peleg Y;Radisky ES;Papo N;Shifman JM
- 通讯作者:Shifman JM
MMP1 drives tumor progression in large cell carcinoma of the lung through fibroblast senescence.
- DOI:10.1016/j.canlet.2021.01.028
- 发表时间:2021-06-01
- 期刊:
- 影响因子:9.7
- 作者:Gabasa M;Radisky ES;Ikemori R;Bertolini G;Arshakyan M;Hockla A;Duch P;Rondinone O;Llorente A;Maqueda M;Davalos A;Gavilán E;Perera A;Ramírez J;Gascón P;Reguart N;Roz L;Radisky DC;Alcaraz J
- 通讯作者:Alcaraz J
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{{ truncateString('Evette S Radisky', 18)}}的其他基金
Exploiting new approaches for selective inhibition of trypsins
开发选择性抑制胰蛋白酶的新方法
- 批准号:
10338695 - 财政年份:2022
- 资助金额:
$ 31.3万 - 项目类别:
Exploiting new approaches for selective inhibition of trypsins
开发选择性抑制胰蛋白酶的新方法
- 批准号:
10542402 - 财政年份:2022
- 资助金额:
$ 31.3万 - 项目类别:
Engineering tissue inhibitor of metalloproteinases-2 (TIMP-2) for triple negative breast cancer therapy
用于三阴性乳腺癌治疗的工程组织金属蛋白酶-2 (TIMP-2) 抑制剂
- 批准号:
10177669 - 财政年份:2021
- 资助金额:
$ 31.3万 - 项目类别:
Engineering tissue inhibitor of metalloproteinases-2 (TIMP-2) for triple negative breast cancer therapy
用于三阴性乳腺癌治疗的工程组织金属蛋白酶-2 (TIMP-2) 抑制剂
- 批准号:
10559719 - 财政年份:2021
- 资助金额:
$ 31.3万 - 项目类别:
Engineering tissue inhibitor of metalloproteinases-2 (TIMP-2) for triple negative breast cancer therapy
用于三阴性乳腺癌治疗的工程组织金属蛋白酶-2 (TIMP-2) 抑制剂
- 批准号:
10357957 - 财政年份:2021
- 资助金额:
$ 31.3万 - 项目类别:
Engineering selective inhibition of metalloproteinases by tissue inhibitors of metalloproteinases (R01 GM132100 RESUB - *TIMPs)
通过金属蛋白酶组织抑制剂对金属蛋白酶进行工程选择性抑制(R01 GM132100 RESUB - *TIMP)
- 批准号:
10319170 - 财政年份:2020
- 资助金额:
$ 31.3万 - 项目类别:
Defining SPINK1 as a tumor driver and therapeutic target in ovarian cancer
将 SPINK1 定义为卵巢癌的肿瘤驱动因素和治疗靶点
- 批准号:
8563720 - 财政年份:2013
- 资助金额:
$ 31.3万 - 项目类别:
Inhibiting serine protease-induced prostate cancer progression
抑制丝氨酸蛋白酶诱导的前列腺癌进展
- 批准号:
8634737 - 财政年份:2013
- 资助金额:
$ 31.3万 - 项目类别:
Defining SPINK1 as a tumor driver and therapeutic target in ovarian cancer
将 SPINK1 定义为卵巢癌的肿瘤驱动因素和治疗靶点
- 批准号:
8685917 - 财政年份:2013
- 资助金额:
$ 31.3万 - 项目类别:
Inhibiting serine protease-induced prostate cancer progression
抑制丝氨酸蛋白酶诱导的前列腺癌进展
- 批准号:
8498656 - 财政年份:2013
- 资助金额:
$ 31.3万 - 项目类别:
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