[R01] Prediction of Biosensors to Small Molecules.
Ente: National Institute of Biomedical Imaging and Bioengineering
Scadenza: 2031-04-30
Importo max: 672.000 EUR
Paese: US
Descrizione
Project Summary-Abstract
Small molecules are central to many aspects of biology: they regulate metabolism, mediate signaling,
serve as biomarkers of disease, and are foundational to most medicines. Yet, unlike nucleic acids or
proteins, small molecules remain largely invisible to real-time observation in living systems. Current
tools, such as mass spectrometry, chromatography, and immunoassays, are powerful but costly,
destructive, and confined to specialized facilities, limiting their utility for dynamic, in situ measurements.
Genetically encoded biosensors exist for a handful of metabolites and ions, but each requires years of
custom engineering and lacks generalizability. As a result, vast regions of the small-molecule
landscape, including key metabolites, signaling molecules, and therapeutic intermediates, remain
inaccessible to direct and continuous measurement.
We propose to overcome this barrier by establishing first an experimental platform and later a predictive
algorithm for creating Synthetic UnaG Biosensors (SUBs). SUBs are a new class of fluorescent
proteins that couple small-molecule recognition directly to an optical signal. UnaG, a naturally occurring
eel protein, is uniquely suited to this role because it fluoresces only when bound to its native ligand,
bilirubin. Unlike conventional biosensors that require engineered linkages between recognition and
reporter domains, UnaG intrinsically produces fluorescence upon ligand binding. By engineering
UnaG’s binding pocket to recognize other diverse small molecules, we will generate vast datasets of
SUB interactions with new small ligands and corresponding fluorescence readouts. These datasets will
be used to train machine learning (ML) models that predict biosensor sequences for new ligands directly
from chemical structure.
The outcome will be thousands (perhaps tens of thousands) of functional SUB:ligand pairs, each linking
protein sequence, ligand identity, and optical response. These biosensors will serve as powerful
reagents for dynamic imaging in living cells, portable diagnostic assays for human health, high-
throughput drug discovery, and monitoring of pollutants such as PFAS and PCBs. Beyond these
applications, the predictive platform itself represents the true innovation: a generalizable, scalable, and
democratized system for small-molecule biosensor discovery. Just as GFP transformed biology by
making proteins visible, this project aims to create the equivalent for small molecules, establishing a
new research modality with the potential to transform biomedical research, diagnostics, and public
health.
Istituzione: UNIVERSITY OF CALIFORNIA, SAN DIEGO
PI: GEOFFREY A CHANG
Progetto: 1R01EB041643-01
Settori: National Institute of Biomedical Imaging and Bioengineering
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