We seek to develop and commercialize a powerful technology platform to increase dramatically the effectiveness of drug-discovery using high-throughput screening (HTS) based on fluorescence lifetime (FLT) readouts of FRET in live cells. This breakthrough is enabled by a combination of two complementary and synergistic technologies: fluorescent biosensor engineering (University of Minnesota, UMN) and fluorescence instrumentation engineering (Fluorescence Innovations, FI). In Phase I we achieved our aims, producing the first truly high-throughput and high-precision applications of FLT in living cells, applied to a specific biosensor (SERCA). We also surpassed our aims by developing new instrumentation for high-throughput spectral recording, carrying out a SERCA screen on a 50,000-compund library, and developing FRET biosensors based on several new targets. In addition, several pharmaceutical companies expressed interest in this technology platform, so UMN and FI started a new drug-discovery company, Photonic Pharma, for the ultimate commercialization of these combined technologies. In Phase II, we will further develop this technology platform and apply it to a diverse array of targets, thus clearly demonstrating the high potential for commercialization. In In Aim 1 we will seek improvements in hardware and software that will enhance future commercialization potential, including a new instrument that combines FLT and spectral recording, increased digitizer speed, higher density plates, connectivity with robotics, and software improvements.
In Aim 2, in order to demonstrate that our technology platform is widely applicable, we will expand our list of biosensors, focusing on targets of high commercial potential, for which world-leading experts are in close proximity at UMN. These disease targets include heart failure, drug abuse and addiction, inflammation and cancer, and muscle dystonia. Biosensors will be engineered and expressed in live cells, and screened against standard test and validation libraries to optimize the screening assay. We will then carry out several large-scale (50,000-compound) screens, using optimized HTS assays. Hit compounds will be retested as a function of compound concentration (dose-response), and then subjected to functional assays performed by the above world-class experts at UMN. Promising hits may become leads for future medicinal chemistry development, but the primary goal is to validate the discovery platform. We are confident that the research conducted under these aims will set us up nicely for the commercialization phase by validating our business plan to combine UMN expertise in biosensor engineering and cell culture with FI expertise in instrumentation, led by Photonic Pharma, an emerging early-phase drug discovery start-up company. Thus our business plan is not to sell instruments, but to leverage our unique combination of biosensor and instrumentation expertise to develop and apply a technology platform that accelerates the early phase of drug discovery.

Public Health Relevance

Fluorescence Innovations, Inc., in collaboration with the University of Minnesota, proposes to greatly improve the technology for drug discovery, during the crucial early stages of the process. This technology has great commercial potential, because it will make the process of drug discovery much more effective and efficient, and is applicable to a wide range of health issues, including heart failure, diabetes, cancer, and drug addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Small Business Technology Transfer (STTR) Grants - Phase II (R42)
Project #
5R42DA037622-04
Application #
9142290
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Pollock, Jonathan D
Project Start
2013-09-01
Project End
2017-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Fluorescence Innovations, Inc.
Department
Type
DUNS #
623858565
City
Minneapolis
State
MN
Country
United States
Zip Code
55414
Guhathakurta, Piyali; Prochniewicz, Ewa; Grant, Benjamin D et al. (2018) High-throughput screen, using time-resolved FRET, yields actin-binding compounds that modulate actin-myosin structure and function. J Biol Chem 293:12288-12298
Rohde, John A; Roopnarine, Osha; Thomas, David D et al. (2018) Mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin. Proc Natl Acad Sci U S A 115:E7486-E7494
Cain, Natalie E; Jahed, Zeinab; Schoenhofen, Amy et al. (2018) Conserved SUN-KASH Interfaces Mediate LINC Complex-Dependent Nuclear Movement and Positioning. Curr Biol 28:3086-3097.e4
Schaaf, Tory M; Peterson, Kurt C; Grant, Benjamin D et al. (2017) High-Throughput Spectral and Lifetime-Based FRET Screening in Living Cells to Identify Small-Molecule Effectors of SERCA. SLAS Discov 22:262-273
Vunnam, Nagamani; Lo, Chih Hung; Grant, Benjamin D et al. (2017) Soluble Extracellular Domain of Death Receptor 5 Inhibits TRAIL-Induced Apoptosis by Disrupting Receptor-Receptor Interactions. J Mol Biol 429:2943-2953
Lo, Chih Hung; Vunnam, Nagamani; Lewis, Andrew K et al. (2017) An Innovative High-Throughput Screening Approach for Discovery of Small Molecules That Inhibit TNF Receptors. SLAS Discov 22:950-961
Rebbeck, Robyn T; Essawy, Maram M; Nitu, Florentin R et al. (2017) High-Throughput Screens to Discover Small-Molecule Modulators of Ryanodine Receptor Calcium Release Channels. SLAS Discov 22:176-186
Rohde, John A; Thomas, David D; Muretta, Joseph M (2017) Heart failure drug changes the mechanoenzymology of the cardiac myosin powerstroke. Proc Natl Acad Sci U S A 114:E1796-E1804
Saunders, Cosmo A; Harris, Nathan J; Willey, Patrick T et al. (2017) TorsinA controls TAN line assembly and the retrograde flow of dorsal perinuclear actin cables during rearward nuclear movement. J Cell Biol 216:657-674
Schaaf, Tory M; Peterson, Kurt C; Grant, Benjamin D et al. (2017) Spectral Unmixing Plate Reader: High-Throughput, High-Precision FRET Assays in Living Cells. SLAS Discov 22:250-261

Showing the most recent 10 out of 12 publications