Persistent Degradation of HER2 Protein by Hybrid nanoPROTAC for Programmed Cell Death

Abstract

Proteolysis-targeting chimera (PROTAC) has emerged as a promising strategy for degrading proteins of interest. Peptide-based PROTACs offer several advantages over small-molecule-based PROTACs, such as high specificity, low toxicity, and large protein–protein interaction surfaces. However, peptide-based PROTACs have several intrinsic shortcomings that strongly limit their application including poor cell permeability and low stability and potency. Herein, we designed a nanosized hybrid PROTAC (GNCTACs) to target and degrade human epidermal growth factor receptor 2 (HER2) in tumor cells. Gold nanoclusters (GNCs) were utilized to connect HER2-targeting peptides and cereblon (CRBN)-targeting ligands. GNCTACs could overcome the intrinsic barriers of peptide-based PROTACs, efficiently delivering HER2-targeting peptides in the cytoplasm and protecting them from degradation. Furthermore, a fasting-mimicking diet was applied to enhance the cellular uptake and proteasome activity. Consequently, more than 95% of HER2 in SKBR3 cells was degraded by GNCTACs, and the degradation lasted for at least 72 h, showing a catalytic-like reaction.

Nano-PROTACs: state of the art and perspectives

“…The split-and-mix PROTAC approach is employed as a special nanoplatform capable of facile screening and self-optimized biomolecule regulation. 15,47,91–95 Specifically, this system consists of independent hydrophilic segments with recruiting targets of POIs and E3 ligases respectively. This strategy (Fig.…”

Click Chemistry and Targeted Degradation: A Winning Combination for Medicinal Chemists?

“…Instead of NPs, Wang et al . proposed the use of gold nanoclusters (GNCs) to increase PROTAC bioavailability, especially for peptide‐based PROTACs [107,108] . A hybrid nanosized PROTAC (GNCTAC) was prepared by combining GNCs to a human epidermal growth factor receptor 2 (HER2) targeting peptide through gold–sulfur coordination.…”

“…Then, GNCs were linked to a conjugation unit terminating with a DBCO moiety, which was combined to a CRBN ligand derivatized with an azide group via a SPAAC reaction. GNCTAC could efficiently accumulate at the tumor site and efficiently degrade HER2, as well as inhibit tumor growth in vivo [108] . Collectively, GNCTACs could overcome the intrinsic limitations of peptide‐based PROTACs (i. e., poor cell permeability and low stability), by efficiently delivering them into cells.…”

Bifunctional Peptide Nanofibrils for Targeted Protein Degradation

“…The self-assembled Nano-PROTAC can efficiently form polynary complexes with multiple supramolecular interactions at high concentrations which directly contribute to the anti-hook effect. Such property makes the Nano-PROTAC distinct from other recent nanoscale PROTAC advancements, including split-and-mix PROTAC (SM-PROTAC), [12] Gold nanocluster PROTAC (GNC-PROTAC), [13] carbon-dot (CD)-based PROTAC (CDTAC) [14] and DNA framework-based PROTAC (DbTAC). [15] The Nano-PROTACs were evaluated in vivo for their tumor-specific localization and retention using animal models.…”