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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.

项目总结