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：
Brett A Colson
金额：
$ 30.65万
依托单位：
PHOTONIC PHARMA, LLC
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：
https://reporter.nih.gov/project-details/10483462
关键词：
Actins Address Adult Affect Affinity Animal Model Anisotropy Arizona Binding Binding Proteins Biochemical Biochemistry Biological Assay Biophysics Biosensor Biotechnology Calorimetry Cardiac Cardiac Myocytes Cardiac Myosins Cell model Cells Collaborations Cyclic AMP-Dependent Protein Kinases Detection Development Doctor of Philosophy Drug Screening Drug Targeting Engineering Fluorescence Fluorescence Resonance Energy Transfer Fluorescent Probes Functional disorder Goals Health Heart Heart failure Hypertrophic Cardiomyopathy In Vitro Leadership Legal patent Letters Libraries Marketing Measurement Methods Molecular Medicine Muscle Proteins Myocardium Myosin ATPase N-terminal Pathologic Patient-Focused Outcomes Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase Phosphorylation Physiological Physiology Problem Solving Protein Conformation Proteins Publications Quality of life Relaxation Research Series Site Small Business Innovation Research Grant Specificity Speed Structure Survival Rate Technology Testing Therapeutic Time Tissues Titrations Treatment Failure Universities Validation Work base blood pump cardiac tissue engineering clinically relevant drug candidate drug discovery efficacy evaluation experience heart function high throughput screening improved in vivo induced pluripotent stem cell innovation instrumentation interest myosin-binding protein C novel novel therapeutics personalized medicine phosphorescence photonics product development protein complex protein function screening small molecule small molecule libraries symptomatic improvement technology development therapeutic development therapeutic 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.

项目概要 Photonic Pharma LLC (PP) 和亚利桑那大学 (UA) 之间的第一阶段 SBIR 合作将为治疗心力衰竭（HF）的创新药物发现活动建立概念验证，靶向心肌肌球蛋白结合蛋白 C (MyBP-C)。迫切需要治疗心力衰竭的新疗法影响美国三分之一成年人的主要健康问题。 MyBP-C 已被确定为治疗靶点纠正高频。磷酸化影响 N 端 MyBP-C 结构，影响其与肌动蛋白和肌球蛋白的结合，调节收缩和放松。因此，用模拟磷酸化的药物靶向 MyBP-C 和/或调节其与肌动蛋白或肌球蛋白的结合是治疗心力衰竭的有前途的方法。聚丙烯有开发基于荧光蛋白生物传感器和高通量筛选（HTS）的专利技术时间分辨荧光寿命（FLT）检测，寻求药物早期突破以前所未有的质量、速度和精度进行发现。 UA 带来 MyBP-C 和心脏方面的专业知识肌肉生物物理学、生物化学和生理学。在一份新出版物中，该合作团队确定了第一个与 MyBP-C 结合并调节其与肌动蛋白相互作用的化合物。该项目的目标是证明 MyBP-C 药物靶向是发现新药物的强大平台影响心肌蛋白功能并最终影响心力衰竭患者预后的疗法。目标1 研究将使用包含 50,000 种不同药物样小分子化合物库的初级 HTS 分析（现在通过最近在一个小型验证库上完成的筛选证明是合理的），使用一种新颖的 FRET 测定，以发现影响 MyBP-C- 与肌动蛋白相互作用的化合物。荧光寿命 FRET (FLT-FRET) 测定使用附着于肌动蛋白和 MyBP-C 结构域 C0-C2 的位点特异性荧光探针。 FLT 测量提供蛋白质结合和构象的精确读数。将评估小分子命中以选择具有最高亲和力相互作用和/或对磷酸化敏感性的化合物。目标 2 研究将使用二次测定（较低通量）以确定 Hit 化合物对功能的功效。选定的化合物将通过生化、生物物理和生理测定来评估对 MyBP-C 功能、肌动蛋白的影响心肌细胞的结合力和收缩力。这些新颖的筛选策略解决了关键的缺失方面，基于早期结构的药物发现，以实现 MyBP-C 治疗开发，根据需要进行精细化调节收缩力并提高患者的生活质量和生存率。在第一阶段，我们将验证 HTS 测定应用于商业规模的药物筛选。在第二阶段，我们将增强效力和特异性药物化学，评估日益增长的生理/病理中最有前途的化合物心力衰竭指征的条件。各大制药公司的来信表明了良好的该技术应用于该特定目标和其他目标的商业潜力。我们的长期目标：解决对经过商业验证的新型心力衰竭疗法的需求尚未得到满足。