Enhanced protein degradation by intracellular delivery of pre-fused PROTACs using lipid-like nanoparticles

Proteolysis-targeting chimaera (PROTAC) technology is an emerging approach for achieving targeted degradation of a protein of interest (POI) intracellularly. However, the cell permeability of PROTACs is limited by their high molecular weight and total polar surface area. Moreover, the activation of...

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Bibliographic Details
Published inJournal of controlled release Vol. 330; pp. 1244 - 1249
Main Authors Chen, Jinjin, Qiu, Min, Ma, Feihe, Yang, Liu, Glass, Zachary, Xu, Qiaobing
Format Journal Article
LanguageEnglish
Published Netherlands Elsevier B.V 10.02.2021
Subjects
Drug delivery
heat-shock protein 70
hydrophobicity
Intercellular Signaling Peptides and Proteins
Lipid-like nanoparticle (LNP)
Lipids
molecular weight
Nanoparticles
permeability
PROTAC
Protein degradation
Proteolysis
surface area
Protein degradation
Drug delivery
PROTAC
Lipid-like nanoparticle (LNP)
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Summary:Proteolysis-targeting chimaera (PROTAC) technology is an emerging approach for achieving targeted degradation of a protein of interest (POI) intracellularly. However, the cell permeability of PROTACs is limited by their high molecular weight and total polar surface area. Moreover, the activation of the proteasome-mediated degradation by PROTAC requires the formation of a ternary (three-component) complex, composed of the PROTAC, the POIs, and E3-ligases related proteins (E3Ps). Simplifying the three-component system to two-component system could theoretically increase the efficiency of the formation of ternary complex and enhance the protein degradation efficiency. Herein, we demonstrate that pre-fusion of PROTACs with E3Ps (called “pre-fused PROTACs”) before administration could transform the original PROTAC system to two-component system. After delivery by lipid nanoparticles, the degradation of POI by pre-fused PROTACs was dramatically increased and accelerated compared with standard PROTACs. Moreover, we demonstrated that this approach could be generalized to another hydrophobic tag (HyT) degrader by demonstrating the improved targeted protein degradation after pre-fusion the HyT degrader with heat shock protein 70 (HSP70). [Display omitted] •Pre-fused PROTACs conveted three component PROTACs to two component systems•Pre-fused ARV-771 delivered by 80-O14B enhanced the degradation of BRD4•Pre-fusion was proved to be a general method for enhancment of protein degradation
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Jinjin Chen: Experimental design and conduction; Data analysis; Writing original draft.
Zachary Glass: Revising the manuscript
Min Qiu.: Lipid synthesis
Feihe Ma: Experimental design
Liu yang: Experimental design
Qiaobing Xu: Supervision, Generating the idea, Revising the manuscript.
ISSN:0168-3659
1873-4995
1873-4995
DOI:10.1016/j.jconrel.2020.11.032