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

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

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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:
Structural Dynamics of Cardiac Muscle Contraction
心肌收缩的结构动力学
  • 批准号:
    8060162
  • 财政年份:
    2011
  • 资助金额:
    $ 30.65万
  • 项目类别:

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