Exploring the Chemical Space of Mycobacterial Oxidative Phosphorylation Inhibitors Using Molecular Modeling DOI Creative Commons
Islam K. Matar,

Zhongmin Dong,

Chérif F. Matta

et al.

ChemMedChem, Journal Year: 2024, Volume and Issue: 19(22)

Published: Sept. 20, 2024

Mycobacteria are opportunistic intracellular pathogens that have plagued humans and other animals throughout history still today. They manipulate hijack phagocytic cells of immune systems, enabling them to occupy this peculiar infection niche. exploit a plethora mechanisms resist antimicrobials (e. g., waxy cell walls, efflux pumps, target modification, biofilms, etc.) thereby evolving into superbugs, such as extensively drug-resistant tuberculosis (XDR TB) bacilli the emerging pathogenic Mycobacterium abscessus complex. This review summarizes action some surging antimycobacterial strategies. Exploiting fact mycobacteria obligate aerobes differences between their oxidative phosphorylation pathways versus human counterpart opens promising avenue for drug discovery. The polymorphism respiratory complexes across mycobacterial imposes challenges on repositioning agents battle rise in nontuberculous infections. In silico strategies exploiting machinery data design novel therapeutic touched upon. potential druggability elements is reviewed. Future research addressing health associated with discussed.

Language: Английский

PROTAC technology: From drug development to probe technology for target deconvolution DOI

Si Yan,

Guangshuai Zhang,

Wei Luo

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 276, P. 116725 - 116725

Published: July 30, 2024

Language: Английский

Citations

19
Restraining the power of Proteolysis Targeting Chimeras in the cage: A necessary and important refinement for therapeutic safety DOI
Renshuai Zhang, Songbo Xie, Jie Ran

et al.

Journal of Cellular Physiology, Journal Year: 2024, Volume and Issue: 239(5)

Published: March 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.

Language: Английский

Citations

10
PROTAC-Based Therapeutics for Targeting HPV Oncoproteins in Head and Neck Cancers DOI Creative Commons
Nobendu Mukerjee, Dibyendu Mukherjee

Nano TransMed, Journal Year: 2025, Volume and Issue: unknown, P. 100071 - 100071

Published: Jan. 1, 2025

Language: Английский

Citations

1
Modulating the phosphorylation status of target proteins through bifunctional molecules DOI

Qindi He,

Zhijie Wang, Rongrong Wang

et al.

Drug Discovery Today, Journal Year: 2025, Volume and Issue: unknown, P. 104307 - 104307

Published: Feb. 1, 2025

Language: Английский

Citations

1
New implications for prion diseases therapy and prophylaxis DOI Creative Commons
Fangzhou Liu, Wenqi Lü, Ling Liu

et al.

Frontiers in Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: March 4, 2024

Prion diseases are rare, fatal, progressive neurodegenerative disorders that affect both animal and human. Human prion mainly present as Creutzfeldt-Jakob disease (CJD). However, there no curable therapies, may negatively the ecosystem human society. Over past five decades, scientists devoting to finding available therapeutic or prophylactic agents for diseases. Numerous chemical compounds have been shown be effective in experimental research on diseases, but with limitations of toxicity, poor efficacy, low pharmacokinetics. The earliest clinical treatments CJD were almost carried out anti-infectious had little amelioration course. With discovery pathogenic misfolding protein (PrPSc) increasing insights into biology, amounts novel technologies attempted eliminate PrPSc. This review presents new perspectives including immunotherapy, gene therapy, small-molecule drug, stem cell therapy. It further explores prospects challenge associated these emerging approaches

Language: Английский

Citations

6
Proteolysis-targeting drug delivery system (ProDDS): integrating targeted protein degradation concepts into formulation design DOI
Yu Chen, Fengyuan Liu,

Samira Pal

et al.

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: 53(19), P. 9582 - 9608

Published: Jan. 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

Language: Английский

Citations

6
Ultrasound Controllable Release of Proteolysis Targeting Chimeras for Triple Negative Breast Cancer Treatment DOI Creative Commons

Hongye He,

Feng Li,

Rui Tang

et al.

Biomaterials Research, Journal Year: 2024, Volume and Issue: 2024

Published: July 10, 2024

Triple-negative breast cancer (TNBC) is a special subtype of cancer, which highly aggressive and incurable. Here, we proposed an ultrasound activatable bromodomain-containing protein 4 (BRD4) proteolysis targeting chimera (PROTAC) release strategy for the first time precisely controlled degradation in preclinical TNBC model. Through combination PROTAC ultrasound-targeted microbubble destruction (UTMD) technology, present also aims to concurrently solve major limitations poor loading capacity microbubbles undesirable membrane permeability PROTAC. (ARV-825)-encapsulated microbubbles, ARV-MBs, were developed efficacious treatment vitro vivo. The synthesized showed ultrasound-responsive drug ability, could effectively promote penetration into tumor site cell. Under ultrasound, ARV-MBs play effective antitumor effect by potentiating ubiquitination BRD4 tumor. current study may provide new idea promoting clinical translation drug-loaded PROTAC, offer therapeutic modality TNBC.

Language: Английский

Citations

4
CRBN‐PROTACs in Cancer Therapy: From Mechanistic Insights to Clinical Applications DOI Open Access
Riya Thapa, Asif Ahmad Bhat, Gaurav Gupta

et al.

Chemical Biology & Drug Design, Journal Year: 2024, Volume and Issue: 104(5)

Published: Nov. 1, 2024

Cereblon (CRBN), a member of the E3 ubiquitin ligase complex, has gained significant attention as therapeutic target in cancer. CRBN regulates degradation various proteins cancer progression, including transcription factors and signaling molecules. PROTACs (proteolysis-targeting chimeras) are novel approach that uses cell's system to remove disease-causing selectively. CRBN-dependent work by tagging harmful for destruction through ubiquitin-proteasome system. This strategy offers several advantages over traditional protein inhibition methods, potential overcome drug resistance. Recent progress developing CRBN-based shown promising preclinical results both hematologic malignancies solid tumors. Additionally, have enhanced our understanding CRBN's role cancer, potentially serving biomarkers patient stratification predicting responses. In this review, we delineate mechanisms action (CRBN-PROTACs), summarize recent advances clinical applications, provide perspective on future development.

Language: Английский

Citations

4
Development of a nano-targeting chimera for the degradation of membrane and cytoplasmic proteins DOI
Peipei Jin, Zhaozheng Chen, Ju Zhang

et al.

Acta Biomaterialia, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

0
Targeted Degradation of ZBP1 with Covalent PROTACs for Anti‐Inflammatory Treatment of Infections DOI Open Access
Riming Huang,

Yusi Hu,

Yifan Wang

et al.

Angewandte Chemie International Edition, Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

Z-DNA binding protein 1 (ZBP1) has emerged as a critical pathogen-sensing that upon activation, triggers necroptotic signaling cascades, leading to potent inflammatory response and potentially causing significant tissue damage. However, available drugs specifically developed for the effective inhibition or degradation of ZBP1 is still lacking so far. In this study, we covalent recognition-based PROTAC (C-PROTAC) molecule ZBP1. It consists DNA aptamer recognition moiety an E3 enzyme-recruiting unit, connected by linker containing N-acyl-N-alkyl sulfonamides (NASA) groups. The binds ZBP1, while NASA-containing facilitates formation bond between target protein. ligase-recruiting unit then directs ubiquitin-proteasome system degrade ZBP1-PROTAC complex. This approach combines high specificity aptamers with efficiency degradation-inducing capabilities PROTACs, providing powerful tool targeted degradation. successful application technology highlights its potential selective elimination disease-associated proteins development novel therapeutic strategies.

Language: Английский

Citations

0