Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Programmable and Conditional Proteolysis Targeting Chimeras Enabled by DNA Nanotechnology

Award Number: R01GM155563
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2028

Group Awards By:

View Award Description

Programmable and Conditional Proteolysis Targeting Chimeras Enabled by DNA Nanotechnology - SUMMARY/ABSTRACT Approximately 85% of the proteome is considered undruggable by traditional, occupancy-driven pharmacology employing small molecular inhibitors. Proteolysis-targeting chimeras (PROTACs) and associated molecules that induce targeted protein degradation via the ubiquitin–proteasome system have emerged as a revolutionary strategy for addressing “undruggable” targets. However, despite the groundbreaking advances and entry of some PROTACs into clinical trials, substantial challenges and considerable room for further development remain. Limitations of current PROTACs include poor cell permeability, limited availability of E3 ligands, and poor selectivity, highlighting a critical need for ongoing innovations in Targeted Protein Degradation (TPD) technology. To address these issues, the possibility of developing an efficacious drug delivery system, coupled with conditional activation of target protein degradation, stands out as a pivotal enhancement. In this context, nucleic acid-based modalities offer considerable promise for advancing TPD, building on the successful biomedical applications of nucleic acid-based drugs like antisense oligonucleotides (ASOs). The programmable and addressable nature of DNA or RNA nanostructures has been successfully harnessed, allowing for functional integration with small molecules, proteins, and peptides to realize applications in drug delivery, vaccines, and biosensors, among others. Based on these prior successes, we hypothesize that by leveraging the inherent programmability and addressability of DNA, precise and effective delivery of protein degradation modalities into cells and conditional activation of degradation can be achieved. For proof-of-concept validation, we have established an efficient cytoplasmic delivery platform utilizing a multifunctional DNA nanodevice and developed a DNA-based target protein degradation system (DTAC) capable of degrading CDK4/6 proteins at nanomolar concentrations. Building on these accomplishments, we intend to integrate our delivery platform with the DNA- based protein degradation system, aiming to pioneer the next generation of TPD technologies. Our approach aims to 1) optimize the programmability of our DNA duplex-based protein degradation system by transitioning from DNA duplex structures to multitargeting DNA nanostructures; 2) assess protein degradation variations caused by spatial distances and evaluate the efficiency of multi-target degradation; 3) integrate and optimize the cytoplasmic DNA nanostructure delivery system with the DNA-based protein degradation system; and 4) validate and optimize the conditional activation of protein degradation through two distinct design approaches: i) toehold mediated conditional activity of DTAC and ii) allosteric mediated conditional activity of DTAC.


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 = $311,214 )
2026	2026	ARIZONA STATE UNIVERSITY	1475 N SCOTTSDALE RD STE 200	SCOTTSDALE	AZ	85257	MARICOPA	USA	Biomedical Research and Research Training	000	3	5/13/2026	NON-COMPETING CONTINUATION	$311,214
														Subtotal = $311,214

Issue Date FY: 2025 ( Subtotal = $312,584 )
2025	2025	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	000	2	5/30/2025	NON-COMPETING CONTINUATION	$312,584
														Subtotal = $312,584

Issue Date FY: 2024 ( Subtotal = $313,852 )
2024	2024	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Biomedical Research and Research Training	000	1	7/8/2024	NEW	$313,852
														Subtotal = $313,852

Grand Total All Awards = $937,650

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Programmable and Conditional Proteolysis Targeting Chimeras Enabled by DNA Nanotechnology

Award Number: R01GM155563

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer