DNA framework-engineered chimeras platform enables selectively targeted protein degradation

Abstract

A challenge in developing proteolysis targeting chimeras (PROTACs) is the establishment of a universal platform applicable in multiple scenarios for precise degradation of proteins of interest (POIs). Inspired by the addressability, programmability, and rigidity of DNA frameworks, we develop covalent DNA framework-based PROTACs (DbTACs), which can be synthesized in high-throughput via facile bioorthogonal chemistry and self-assembly. DNA tetrahedra are employed as templates and the spatial position of each atom is defined. Thus, by precisely locating ligands of POI and E3 ligase on the templates, ligand spacings can be controllably manipulated from 8 Å to 57 Å. We show that DbTACs with the optimal linker length between ligands achieve higher degradation rates and enhanced binding affinity. Bispecific DbTACs (bis-DbTACs) with trivalent ligand assembly enable multi-target depletion while maintaining highly selective degradation of protein subtypes. When employing various types of warheads (small molecules, antibodies, and DNA motifs), DbTACs exhibit robust efficacy in degrading diverse targets, including protein kinases and transcription factors located in different cellular compartments. Overall, utilizing modular DNA frameworks to conjugate substrates offers a universal platform that not only provides insight into general degrader design principles but also presents a promising strategy for guiding drug discovery.

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] …”

“…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. The injected Nano-PROTAC was able to quickly accumulate at tumor sites within 30 min and retain its localization for up to 72 h, and such tumor enrichment and retention was time-and dose-dependent.…”

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] …”

A photoactivatable upconverting nanodevice boosts the lysosomal escape of PROTAC degraders for enhanced combination therapy

“…22–24 These nanocarriers offer significant advantages by enabling precise delivery of drugs to targeted locations, thereby maximizing the therapeutic efficacy while minimizing systemic side effects. 25 Moreover, the encapsulation of various drugs within a single nanocarrier allows for their synchronized release at specific sites of action, enhancing the potential for synergistic anti-tumor effects. 26 Therefore, nanocarrier systems are particularly advantageous for delivering PROTACs, 27 as they effectively overcome challenges such as high hydrophobicity and limited cell membrane permeability that are typical of traditional PROTACs.…”