High-throughput discovery platform for… (R43HL162329) – Project Grant to Photonic Pharma LLC

Abstract: 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.

Action	Obligated	Date
Amendment	$0	Aug 14, 2024
Amendment	$306,471	Apr 6, 2022
Original award	$306,471	Apr 6, 2022

High-throughput discovery platform for modulators of cardiac muscle proteins to treat heart failure

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