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De novo design of a generalizable protein biosensor platform for point-of-care testing

Award Number: R00EB031913
ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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De novo design of a generalizable protein biosensor platform for point-of-care testing - úú PROJECT SUMMARY/ABSTRACT Delivering diagnostic services at the point-of-care (POC) can improve the quality of healthcare in clinics, in emergency settings, or at home, which can potentially ease hospitals’ burden, for instance, during the COVID- 19 pandemic. Precision and personalized medicine revolution also require POC testing to provide readily available biomarker information to clinicians. The goal of this career development proposal is to create fast, inexpensive, sensitive, and reliable molecular diagnostics to address the 21st-century healthcare challenges. The central hypothesis is that we can efficiently utilize computational protein design to create modular allosteric protein switches, named LOCKR (Latching Orthogonal Cage–Key pRotein), that enable the rapid and reversible conformational changes upon interaction. As a proof of principle, we demonstrate that LOCKR- based biosensors can be configured to produce bioluminescence upon the addition of clinical targets (e.g., botulinum toxin, cardiac troponin I, HER2 receptor, Fc domain, anti-HBV mAb, anti-SARS-CoV2 antibodies, and SARS-CoV2 receptor-binding domain/spike protein, Fig 1 and 2) in homogeneous “all-in-solution” assays. Due to the modularity of LOCKR sensor platform and the advance in de novo binder design for arbitrary protein targets, we proposed the integration of both features as the universal strategy to develop tailored biosensors for user-defined targets. The main specific aims for the independent phase are to iteratively expand LOCKR-based diagnostics with the synergy of (1) de novo protein binder design to directly detect various disease protein biomarkers, and (2) indirectly detect the antibodies that compete with the designed interface, as POC devices; and (3) to repurpose the original luminescence signal with other compatible readouts by exchanging the reporter modules. For more specific proof-of-concept projects during the mentored phase, I describe in Aim 1 the use of state-of-the-art computational protein design methods to create an interleukin-6 binder and biosensor. In Aim 2, I propose a general way to develop antibody biosensors by demonstrating COVID-19 serological tests as an example. With my expertise in biosensor engineering, I attempt in Aim 3 to develop a ratiometric bioluminescence resonance energy transfer (BRET) biosensor to analyze the HBV antibody and a colorimetric biosensor to measure human cardiac troponin I level. Ultimately, I anticipate this new sensor platform is significant for the development of robust protein sensors that will be broadly applicable to arbitrary targets and enabling its POC compatible readouts for future diagnostics.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	4	3/4/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $249,000 )
2025	2025	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	4	5/27/2025	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $249,000

Issue Date FY: 2024 ( Subtotal = $249,000 )
2024	2024	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	3	6/5/2024	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $249,000

Issue Date FY: 2023 ( Subtotal = $249,000 )
2023	2023	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	5/23/2023	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $747,000

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De novo design of a generalizable protein biosensor platform for point-of-care testing

Award Number: R00EB031913

ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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