Nano-PROTACs: state of the art and perspectives

Nanoscale, Год журнала: 2024, Номер 16(9), С. 4378 - 4391

Опубликована: Янв. 1, 2024

Schematic illustration of the combinational strategy nanotechnology and PROTACs (Nano-PROTACs): typical shortcomings traditional nanotechnology-based strategies for PROTAC drugs optimization.

Язык: Английский

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Proteolysis Targeting Chimera Degraders of the METTL3–14 m⁶A-RNA Methyltransferase

JACS Au, Год журнала: 2024, Номер 4(2), С. 713 - 729

Опубликована: Фев. 12, 2024

Methylation of adenine N6 (m6A) is the most frequent RNA modification. On mRNA, it catalyzed by METTL3–14 heterodimer complex, which plays a key role in acute myeloid leukemia (AML) and other types blood cancers solid tumors. Here, we disclose first proteolysis targeting chimeras (PROTACs) for an epitranscriptomics protein. For designing PROTACs, made use crystal structure complex with potent selective small-molecule inhibitor (called UZH2). The optimization linker started from desfluoro precursor UZH2 whose synthesis more efficient than that UZH2. nine PROTAC molecules featured PEG- or alkyl-based linkers, but only latter showed cell penetration. With this information hand, synthesized 26 PROTACs based on alkyl linkers different lengths rigidity. formation ternary was validated FRET-based biochemical assay vitro ubiquitination assay. 14, 20, 22, 24, 30, featuring lengths, 50% higher degradation METTL3 and/or METTL14 measured Western blot MOLM-13 cells. They also substantial three AML lines prostate cancer line PC3.

Язык: Английский

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Restraining the power of Proteolysis Targeting Chimeras in the cage: A necessary and important refinement for therapeutic safety

Journal of Cellular Physiology, Год журнала: 2024, Номер 239(5)

Опубликована: Март 19, 2024

Abstract Proteolysis Targeting Chimeras (PROTACs) represent a significant advancement in therapeutic drug development by leveraging the ubiquitin‐proteasome system to enable targeted protein degradation, particularly impacting oncology. This review delves into various types of PROTACs, such as peptide‐based, nucleic acid‐based, and small molecule each addressing distinct challenges degradation. It also discusses innovative strategies like bridged PROTACs conditional switch‐activated offering precise targeting previously “undruggable” proteins. The potential extends beyond oncology, with ongoing research technological advancements needed maximize their potential. Future progress this field relies on interdisciplinary collaboration integration advanced computational tools open new treatment avenues across diseases.

Язык: Английский

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Intracellular Chemical Reaction‐Induced Self‐Assembly for the Construction of Artificial Architecture and Its Functions

Advanced NanoBiomed Research, Год журнала: 2024, Номер 4(4)

Опубликована: Фев. 6, 2024

Intracellular assemblies play vital roles in maintaining cellular functions through structural recognition‐mediated interactions. The introduction of artificial structures has garnered substantial interest modulating via activation/inhibition interactions with biomacromolecules. However, the uptake these high‐molecular‐weight may limit their performance. Recently, intracellular chemical‐reaction‐induced self‐assembly emerged as a promising strategy for generating situ nanostructures biofunctionalities interacting This approach addresses challenge synthetic reactions occurring complex environments by utilizing diverse chemical that respond to endogenous and exogenous stimuli. review provides an overview latest advancements techniques. It focuses on responsiveness specific conditions, such redox overexpressed enzymes. Additionally, initiation stimuli, including reagents irradiation is explored. Polymerization‐induced hydrophobicity highlighted, leading into micro‐/nanostructures. These processes contribute construction materials morphologies, offering versatile functionalities biological applications.

Язык: Английский

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Liposomal STAT3-Degrading PROTAC Prodrugs Promote Anti-Hepatocellular Carcinoma Immunity via Chemically Reprogramming Cancer Stem Cells

Nano Letters, Год журнала: 2024, Номер unknown

Опубликована: Апрель 10, 2024

Cancer stem cells (CSCs) with hyperactivated signal transducer and activator of transcription 3 (STAT3) are a major driver hepatocellular carcinoma (HCC). Herein, we report nanointegrative proteolysis-targeting chimera (PROTAC)-based STAT3 degradation strategy that enables efficient chemical reprogramming HCC-associated CSCs, which potently inhibits CSC growth while evoking anti-HCC immune responses. The PROTAC prodrug was synthesized by conjugating the binding domain (inS3) thioketal-caged E3 ligase ligand (VL-TK) via an oligo(ethylene glycol) linker (OEG) tuned length flexibility encapsulating it in cRGD-modified cationic liposomes for CSC-targeted delivery facilitating their lysosomal escape. prodrugs were activated upregulated ROS levels CSCs efficiently degraded reprogramming, would not only impair stemness features but also remodel immunosuppressive TME into immunosupportive state to boost immunity. This provides approach improving HCC treatment clinics.

Язык: Английский

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Cathepsin B Responsive Peptide–Purpurin Conjugates Assembly-Initiated in Situ Self-Aggregation for Cancer Sonotheranostics

Nano Letters, Год журнала: 2024, Номер 24(3), С. 950 - 957

Опубликована: Янв. 10, 2024

Sonodynamic therapy (SDT) was hampered by the sonosensitizers with low bioavailability, tumor accumulation, and therapeutic efficiency. In situ responsive sonosensitizer self-assembly strategy may provide a promising route for cancer sonotheranositics. Herein, an intelligent sonotheranostic peptide–purpurin conjugate (P18-P) is developed that can self-assemble into supramolecular structures via self-aggregation triggered rich enzyme cathepsin B (CTSB). After intravenous injection, versatile probe could achieve deep tissue penetration because of sequence P18-P. More importantly, CTSB-triggered strongly prolonged retention time, amplified photoacoustic imaging signal sensitive CTSB detection, boosted reactive oxygen species advanced SDT, evoking specific sonotheranostics. This serve as efficient platform early diagnosis activity effective therapy.

Язык: Английский

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Rational strategies for improving the efficiency of design and discovery of nanomedicines

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Ноя. 18, 2024

Abstract The rise of rational strategies in nanomedicine development, such as high-throughput methods and computer-aided techniques, has led to a shift the design discovery patterns nanomedicines from trial-and-error mode mode. This transition facilitates enhancement efficiency preclinical pipeline nanomaterials, particularly improving hit rate nanomaterials optimization promising candidates. Herein, we describe directed evolution driven by data accelerate with high delivery efficiency. Computer-aided are introduced detail one cutting-edge directions for development nanomedicines. Ultimately, look forward expanding tools using multidisciplinary approaches. Rational may potentially boost next-generation

Язык: Английский

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Copper‐Induced Supramolecular Peptide Assemblies for Multi‐pathway Cell Death and Tumor Inhibition

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(34)

Опубликована: Июнь 5, 2024

Although self-assembly has emerged as an effective tool for fabricating biomaterials, achieving precise control over the morphologies and functionalities of resultant assemblies remains ongoing challenge. Inspired by copper peptide naturally present in human plasma, this study, we designed a synthetic precursor, FcGH. FcGH can self-assemble via two distinct pathways: spontaneous Cu

Язык: Английский

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Progress of proteolysis-targeting chimeras (PROTACs) delivery system in tumor treatment

International Journal of Biological Macromolecules, Год журнала: 2024, Номер 275, С. 133680 - 133680

Опубликована: Июль 4, 2024

Proteolysis targeting chimeras (PROTACs) can use the intrinsic protein degradation system in cells to degrade pathogenic target proteins, and are currently a revolutionary frontier of development strategy for tumor treatment with small molecules. However, poor water solubility, low cellular permeability, off-target side effects most PROTACs have prevented them from passing preclinical research stage drug development. This requires appropriate delivery systems overcome these challenging hurdles ensure precise towards site. Therefore, combination multifunctional will open up new directions targeted proteins. In this review, we systematically reviewed design principles recent advances various systems. Moreover, constructive strategies developing were proposed comprehensively. review aims deepen understanding drugs promote further system.

Язык: Английский

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Proteolysis-targeting drug delivery system (ProDDS): integrating targeted protein degradation concepts into formulation design

Chemical Society Reviews, Год журнала: 2024, Номер 53(19), С. 9582 - 9608

Опубликована: Янв. 1, 2024

Targeted protein degradation (TPD) has emerged as a revolutionary paradigm in drug discovery and development, offering promising avenue to tackle challenging therapeutic targets. Unlike traditional approaches that focus on inhibiting function, TPD aims eliminate proteins of interest (POIs) using modular chimeric structures. This is achieved through the utilization proteolysis-targeting chimeras (PROTACs), which redirect POIs E3 ubiquitin ligases, rendering them for by cellular ubiquitin-proteasome system (UPS). Additionally, other technologies such lysosome-targeting (LYTACs) autophagy-based degraders facilitate transportation endo-lysosomal or autophagy-lysosomal pathways degradation, respectively. Despite significant growth preclinical research, many fail progress beyond this stage development. Various factors contribute limited success agents, including hurdle inadequate delivery target site. Integrating into platforms could surmount challenges

Язык: Английский

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