Targeted Biomolecule Regulation Platform: A Split-and-Mix PROTAC Approach

Abstract

The development of bifunction al molecules, which can enable targeted RNA degradation, targeted protein acetylation, or targeted protein degradation, remains a time-consuming process that requires tedious optimization. We propose a split-and-mix nanoplatform that serves as a self-adjustable platform capable of facile screening, programmable ligand ratios, self-optimized biomolecule spatial recognition, and multifunctional applications. Herein, we demonstrate the potential of our proposed nanoplatform by showcasing proteolysis-targeting chimeras (PROTACs), namely, split-and-mix PROTAC (SM-PROTAC). We highlight the scope of our platform through the targeted disruption of intracellular therapeutic targets involving ERα, CDK4/6, AR, MEK1/2, BRD2/4, BCR-ABL, etc. These studies confirm the effectiveness and universality of the SM-PROTAC platform for proximity-induced applications. This platform is programmable, with significant potential applications to biomolecule regulation, including the fields of epigenetics, gene editing, and biomolecule modification regulation.

Nano Proteolysis Targeting Chimeras (PROTACs) with Anti‐Hook Effect for Tumor Therapy

“…[12] Thus, ATNbased PROTACs is a practical biotechnology to overcome the reduced in vivo efficacy of traditional small molecule PROTACs, which can counteract "hook effect" by constructing effective polynary complexes ((E3) m : PROTAC: (POI) n ). [13] Moreover, in situ activated ATN-based PRO-TACs can further make up for the severe off-target induced unintended tissue effect of traditional PROTACs [14] in tumor therapies. In situ self-assembly of peptides in animal, firstly reported in 2015 by our group, [15] which is a well-developed strategy for specific construction of ATNs, can not only achieve morphology adjustability [16] mediated by stimuliresponses [17] and ligand-receptor interactions, but also facilitate dose-dependent assembly and retention, ultimately supplying a structural basis to realize hybrid biofunctions including specific diagnosis and theranostics.…”

Selective Protein of Interest Degradation through the Split-and-Mix Liposome Proteolysis Targeting Chimera Approach

“…, − Additionally, their fixed ratio of modules for recruiting E3 ligase and target protein faces challenges in adjustment. To address these challenges, we developed a novel peptide-based self-assembly PROTAC nanoplatform (SM-PROTAC) which is equipped with features including facile screening, programmable ligand ratios, self-optimized biomolecule spatial recognition, and multifunctional applications (Scheme B) . However, the low drug efficacy of peptide-based SM-PROTAC limits its further development in the biomedical field.…”

“…With this platform, the amino group of the DSPE-PEG2000-NHS compound serves as an attachment site for the molecule of the E3 ligase and the POI ligand. Additionally, utilizing PEG as the hydrophilic end molecule, the E3 recruiters and POI recruiters are randomly exposed on the surface of the nanosphere at a facilely regulated ligand ratio, bringing E3 ligase close to the target proteins at spatial . Furthermore, LipoSM-PROTAC’s advantages are as follows: (1) self-regulated ligand ratios; (2) excellent biocompatibility and biodegradability; (3) multiple ligands (recruit multiple ligand-binding proteins); (4) targeted delivery ability; (5) stable structure; (6) excellent potential for clinical applications with high drug efficacy.…”

Delivering on Cell‐Selective Protein Degradation Using Chemically Tailored PROTACs

“…One major hurdle lies in the inability to selectively control protein degradation within specific types of cells and in a spatiotemporal manner. [22,23] Furthermore, the systemic administration of PROTACs can potentially lead to in vivo toxicity and off-target protein degradation. [2,[24][25][26] These limitations underscore the importance of developing methods for cell-selective and controlled protein degradation, which can facilitate the study of protein function in biological systems and hold promise for treating genetic disorders, such as cancers and neurodegenerative diseases.…”

“…Despite the recent advancements in designing PROTACs for targeted protein degradation, there are still significant challenges in maximizing their therapeutic efficacy. One major hurdle lies in the inability to selectively control protein degradation within specific types of cells and in a spatiotemporal manner [22,23] . Furthermore, the systemic administration of PROTACs can potentially lead to in vivo toxicity and off‐target protein degradation [2,24–26] .…”