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Intracellular Delivering E3P-ligand conjugates to induce efficient protein degradation

Award Number: R01GM164302
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: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2030

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Intracellular Delivering E3P-ligand conjugates to induce efficient protein degradation - Abstract The activation of the proteasome-mediated degradation by PROTAC requires the formation of a ternary (three- component) complex, composed of the PROTAC, the target protein, and E3-ligases related proteins (E3Ps). At elevated concentrations, PROTAC molecules have the potential to saturate binding sites on either the protein target or the E3 ligase without establishing the essential ternary complex (E3P:PROTAC:target) essential for ubiquitination and subsequent degradation. This is called “Hook effect”, which leads to a decrease in activity and provides a protective shield against induced degradation. It poses challenges in clinical studies when choosing optimal dosing regimens. Here we propose to develop new approaches that can transform the classical three- component PROTAC system into a binary system, avoid the hook effect and improve protein degradation efficiency. One approach is to covalently conjugate a ligand that binds to target protein to an E3 ubiquitin ligase and deliver the E3P-Ligand conjugates intracellularly using an LNP to induce target protein degradation through ubiquitin proteosome pathway. Another approach is to pre-mix PROTAC and E3P to form pre-fused PROTAC (E3P:PROTAC) which is then delivered intracellularly using LNPs. Aim 1. Covalent conjugation of ligand for target protein onto E3P Aim 2. In vitro and in vivo study of LNP mediated delivery of pre-fused E3P (E3P:PROTAC) Aim 3. In vivo study of PROTAC delivery for reversing liver fibrosis in mouse model The scientific and preclinical impact of this project are 1) development of more efficient approach for target protein degradation using ubiquitin proteosome system; 2) proof-of-concept that directly conjugating a ligand for target protein on E3 ligase is effective for degradation of target protein. 3) the success of this study will open a new paradigm of target protein degradation. The proposed research could also lead to new treatment for liver fibrosis by targeted degradation of BRD4 using advanced PROTAC delivery technologies.


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 = $1,243,500 )
2026	2026	TRUSTEES OF TUFTS COLLEGE	80 GEORGE ST	MEDFORD	MA	02155	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	7/29/2026	NEW	$1,243,500
														Subtotal = $1,243,500

Grand Total All Awards = $1,243,500

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Intracellular Delivering E3P-ligand conjugates to induce efficient protein degradation

Award Number: R01GM164302

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: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2030

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