High-throughput discovery platform for modulators of cardiac muscle proteins to treat heart failure
用于治疗心力衰竭的心肌蛋白调节剂的高通量发现平台
基本信息
- 批准号:10483462
- 负责人:
- 金额:$ 30.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-15 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsAddressAdultAffectAffinityAnimal ModelAnisotropyArizonaBindingBinding ProteinsBiochemicalBiochemistryBiological AssayBiophysicsBiosensorBiotechnologyCalorimetryCardiacCardiac MyocytesCardiac MyosinsCell modelCellsCollaborationsCyclic AMP-Dependent Protein KinasesDetectionDevelopmentDoctor of PhilosophyDrug ScreeningDrug TargetingEngineeringFluorescenceFluorescence Resonance Energy TransferFluorescent ProbesFunctional disorderGoalsHealthHeartHeart failureHypertrophic CardiomyopathyIn VitroLeadershipLegal patentLettersLibrariesMarketingMeasurementMethodsMolecular MedicineMuscle ProteinsMyocardiumMyosin ATPaseN-terminalPathologicPatient-Focused OutcomesPatientsPharmaceutical ChemistryPharmaceutical PreparationsPharmacologic SubstancePhasePhosphorylationPhysiologicalPhysiologyProblem SolvingProtein ConformationProteinsPublicationsQuality of lifeRelaxationResearchSeriesSiteSmall Business Innovation Research GrantSpecificitySpeedStructureSurvival RateTechnologyTestingTherapeuticTimeTissuesTitrationsTreatment FailureUniversitiesValidationWorkbaseblood pumpcardiac tissue engineeringclinically relevantdrug candidatedrug discoveryefficacy evaluationexperienceheart functionhigh throughput screeningimprovedin vivoinduced pluripotent stem cellinnovationinstrumentationinterestmyosin-binding protein Cnovelnovel therapeuticspersonalized medicinephosphorescencephotonicsproduct developmentprotein complexprotein functionscreeningsmall moleculesmall molecule librariessymptomatic improvementtechnology developmenttherapeutic developmenttherapeutic target
项目摘要
Project Summary
This Phase I SBIR collaboration between Photonic Pharma LLC (PP) and the University of Arizona (UA)
will establish proof-of-concept for an innovative drug-discovery campaign for treatment of heart failure (HF),
targeting cardiac myosin-binding protein C (MyBP-C). There is an urgent need for novel therapies for HF, a
major health problem affecting 1 in 30 adults in the US. MyBP-C has been identified as a therapeutic target for
correcting HF. Phosphorylation affects N-terminal MyBP-C structure, affecting its binding to actin and myosin,
modulating contraction and relaxation. Therefore, targeting MyBP-C with drugs that mimic phosphorylation
and/or modulate its binding to actin or myosin is a promising approach to treatment of heart failure. PP has
developed patented technology for fluorescent protein biosensors and high-throughput screening (HTS) based
on time-resolved fluorescence lifetime (FLT) detection, seeking breakthroughs in the early phase of drug
discovery with unprecedented quality, speed, and precision. UA brings expertise in MyBP-C and cardiac
muscle biophysics, biochemistry, and physiology. In a new publication, this collaborative team has identified
the first compounds that bind to MyBP-C and modulate its interaction with actin. The goal of this project is to
demonstrate proof-of-concept that drug targeting of MyBP-C is a powerful platform for discovery of novel
therapies to affect cardiac muscle protein function and ultimately patient outcomes in heart failure. Aim 1
studies will use a primary HTS assay of a 50,000-compound library of diverse and drug-like small molecules
(now justified by recently completed screens on a small validation library), using a novel FRET assay, to find
compounds that affect the interaction of MyBP-C-with actin. The fluorescence lifetime FRET (FLT-FRET)
assay uses site-specific fluorescent probes attached to actin and MyBP-C domains C0-C2. FLT measurements
provide a precise readout of protein binding and conformation. Small-molecule Hits will be evaluated to select
compounds with highest affinity interactions and/or sensitivity to phosphorylation. Aim 2 studies will use
secondary assays (lower throughput) to determine efficacy of Hit compounds on function. Selected compounds
will be evaluated by biochemical, biophysical, and physiological assays for effects on MyBP-C function, actin
binding, and contractility in cardiac cells. These novel screening strategies address the key missing aspect,
early-phase structure-based drug discovery, to enable MyBP-C therapeutic development, as needed to fine-
tune contractility and improve patient quality of life and survival. In Phase I we will validate the HTS assay for
application to commercial-scale drug screening. In Phase II we will enhance potency and specificity with
medicinal chemistry, evaluating the most promising compounds in increasingly physiological/pathological
conditions for the heart failure indication. Letters from major pharmaceutical companies indicate great
commercial potential for this technology, applied to this specific target and others. Our long-term goal: address
the unmet need for novel heart failure therapies that are commercially validated.
项目总结
项目成果
期刊论文数量(0)
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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Brett A Colson其他文献
Brett A Colson的其他文献
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{{ truncateString('Brett A Colson', 18)}}的其他基金
Diversity Supplement to Skeletal Myosin-Binding Protein C Regulation and Structural Dynamics
骨骼肌球蛋白结合蛋白 C 调节和结构动力学的多样性补充
- 批准号:
10824055 - 财政年份:2022
- 资助金额:
$ 30.65万 - 项目类别:
Skeletal Myosin-Binding Protein C Regulation and Structural Dynamics
骨骼肌球蛋白结合蛋白 C 调节和结构动力学
- 批准号:
10666442 - 财政年份:2022
- 资助金额:
$ 30.65万 - 项目类别:
Skeletal Myosin-Binding Protein C Regulation and Structural Dynamics
骨骼肌球蛋白结合蛋白 C 调节和结构动力学
- 批准号:
10442876 - 财政年份:2022
- 资助金额:
$ 30.65万 - 项目类别:
Diversity Supplement to Structural Dynamics of Cardiac Myosin-Binding Protein C Regulation
心肌肌球蛋白结合蛋白 C 调节结构动力学的多样性补充
- 批准号:
10412720 - 财政年份:2021
- 资助金额:
$ 30.65万 - 项目类别:
Structural Dynamics of Cardiac Myosin-Binding Protein C Regulation
心肌肌球蛋白结合蛋白 C 调节的结构动力学
- 批准号:
10545008 - 财政年份:2019
- 资助金额:
$ 30.65万 - 项目类别:
Structural Dynamics of Cardiac Myosin-Binding Protein C Regulation
心肌肌球蛋白结合蛋白 C 调节的结构动力学
- 批准号:
10090620 - 财政年份:2019
- 资助金额:
$ 30.65万 - 项目类别:
Structural Dynamics of Cardiac Myosin-Binding Protein C Regulation
心肌肌球蛋白结合蛋白 C 调节的结构动力学
- 批准号:
10320335 - 财政年份:2019
- 资助金额:
$ 30.65万 - 项目类别:
Structural Dynamics of Cardiac Myosin Binding Protein-C
心肌肌球蛋白结合蛋白-C 的结构动力学
- 批准号:
8791218 - 财政年份:2014
- 资助金额:
$ 30.65万 - 项目类别:
Structural Dynamics of Cardiac Myosin Binding Protein-C
心肌肌球蛋白结合蛋白-C 的结构动力学
- 批准号:
9129782 - 财政年份:2014
- 资助金额:
$ 30.65万 - 项目类别:
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