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

• 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
• 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

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.

项目摘要 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）。目前迫切需要一种新的治疗HF的方法， 在美国，每30个成年人中就有一个受到严重的健康问题的影响。MyBP-C已被确定为治疗靶点， 校正HF。磷酸化影响N-末端MyBP-C结构，影响其与肌动蛋白和肌球蛋白的结合， 调节收缩和舒张。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希望的方法。PP具有 开发了荧光蛋白生物传感器和高通量筛选（HTS）的专利技术， 在时间分辨荧光寿命（FLT）检测上，寻求药物早期的突破 以前所未有的质量、速度和精度进行探索。UA带来了MyBP-C和心脏领域的专业知识 肌肉生物物理学、生物化学和生理学。在一份新的出版物中，这个合作团队已经确定了 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 证明了MyBP-C的药物靶向是发现新药物的有力平台。 影响心肌蛋白功能和最终患者心力衰竭结局的治疗。要求1 这些研究将使用一个包含50，000种不同的药物样小分子化合物库的初级HTS分析 (now通过最近完成的小验证库筛选证明），使用新的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） 测定使用连接到肌动蛋白和MyBP-C结构域C 0-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。将对小分子命中进行评价，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。Aim 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。选化合物 将通过生物化学、生物物理学和生理学试验评估对MyBP-C功能、肌动蛋白 结合和心肌细胞的收缩性。这些新的筛选策略解决了关键的缺失方面， 早期阶段基于结构的药物发现，以使MyBP-C治疗开发，根据需要精细- 调节收缩力并改善患者的生活质量和存活率。在第一阶段，我们将验证HTS检测试剂盒， 用于商业规模的药物筛选。在第二阶段，我们将提高效力和特异性， 药物化学，评估最有前途的化合物在越来越多的生理/病理 心力衰竭适应症的条件。来自各大制药公司的信件表明， 这项技术的商业潜力，适用于这个特定的目标和其他人。我们的长期目标：解决 对商业验证的新型心力衰竭疗法的未满足需求。