The progress of molecules and strategies for the treatment of HBV infection DOI Creative Commons

Youlu Pan,

Heye Xia,

Yanwen He

et al.

Frontiers in Cellular and Infection Microbiology, Journal Year: 2023, Volume and Issue: 13

Published: March 15, 2023

Hepatitis B virus infections have always been associated with high levels of mortality. In 2019, hepatitis (HBV)-related diseases resulted in approximately 555,000 deaths globally. view its lethality, the treatment HBV has presented a huge challenge. The World Health Organization (WHO) came up ambitious targets for elimination as major public health threat by 2030. To accomplish this goal, one WHO’s strategies is to develop curative treatments infections. Current clinical setting included 1 year pegylated interferon alpha (PEG-IFNα) and long-term nucleoside analogues (NAs). Although both demonstrated outstanding antiviral effects, it difficult cure HBV. reason that covalently closed circular DNA (cccDNA), integrated DNA, viral burden, impaired host immune responses all hinder development overcome these problems, there are trials on number molecules being carried out, -showing promising results so far. review, we summarize functions mechanisms action various synthetic molecules, natural products, traditional Chinese herbal medicines, clustered regularly interspaced short palindromic repeats their proteins (CRISPR/Cas)-based systems, zinc finger nucleases (ZFNs), transcription activator-like effector (TALENs), which could destroy stability life cycle. addition, discuss modulators, can enhance or activate system, well some representative products anti-HBV effects.

Language: Английский

Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies DOI Creative Commons
Jifa Zhang, Yinglu Zhang, Jiaxing Wang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Language: Английский

Citations

197
Chemistries of bifunctional PROTAC degraders DOI
Chao-Guo Cao,

Ming He,

Liguo Wang

et al.

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(16), P. 7066 - 7114

Published: Jan. 1, 2022

Proteolysis targeting chimeras (PROTACs) technology is a novel and promising therapeutic strategy using small molecules to induce ubiquitin-dependent degradation of proteins.

Language: Английский

Citations

178
PROTAC technology: A new drug design for chemical biology with many challenges in drug discovery DOI Creative Commons
Nicolas Guedeney, Marie Cornu, Florian Schwalen

et al.

Drug Discovery Today, Journal Year: 2022, Volume and Issue: 28(1), P. 103395 - 103395

Published: Oct. 10, 2022

Language: Английский

Citations

74
A Physiologically Responsive Nanocomposite Hydrogel for Treatment of Head and Neck Squamous Cell Carcinoma via Proteolysis‐Targeting Chimeras Enhanced Immunotherapy DOI
Yaping Wu,

Xiaowei Chang,

Guizhu Yang

et al.

Advanced Materials, Journal Year: 2023, Volume and Issue: 35(12)

Published: Jan. 19, 2023

Although immunotherapy has revolutionized oncotherapy, only ≈15% of head and neck squamous cell carcinoma (HNSCC) patients benefit from the current therapies. An immunosuppressive tumor microenvironment (TME) dysregulation polycomb ring finger oncogene BMI1 are potential reasons for failure. Herein, to promote immunotherapeutic efficacy against HNSCC, an injectable nanocomposite hydrogel is developed with a polymer framework (PLGA-PEG-PLGA) that loaded both imiquimod encapsulated CaCO3 nanoparticles (RC) cancer membrane (CCM)-coated mesoporous silica containing peptide-based proteolysis-targeting chimeras (PROTAC) paclitaxel (PepM@PacC). Upon injection, this undergoes in situ gelation, after which it degrades TME over time, releasing RC PepM@PacC respectively perform chemotherapy. Specifically, particles selectively manipulate tumor-associated macrophages dendritic cells activate T-cell immune response, while CCM-mediated homologous targeting endocytosis delivers into cells, where endogenous glutathione promotes disulfide bond cleavage release PROTAC peptide degradation frees particle pores elicit apoptosis meanwhile enhance immunotherapy. Thus, hydrogel, designed exploit multiple known vulnerabilities succeeds suppressing growth metastasis HNSCC.

Language: Английский

Citations

60
Self-Assembled Nano-PROTAC Enables Near-Infrared Photodynamic Proteolysis for Cancer Therapy DOI
Weishan Wang,

Chenghong Zhu,

Bin Zhang

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(30), P. 16642 - 16649

Published: July 21, 2023

Confining the protein degradation activity of proteolysis-targeting chimera (PROTAC) to cancer lesions ensures precision treatment. However, it still remains challenging precisely control PROTAC function in tumor regions vivo. We herein describe a near-infrared (NIR) photoactivatable nano-PROTAC (NAP) for remote-controllable proteolysis tumor-bearing mice. NAP is formed by molecular self-assembly from an amphiphilic conjugate linked with NIR photosensitizer through singlet oxygen (1O2)-cleavable linker. The initially silenced but can be remotely switched on upon photoirradiation generate 1O2 photosensitizer. demonstrated that enabled tumor-specific bromodomain-containing 4 (BRD4) light-instructed manner. This combination photodynamic therapy (PDT) elicited effective suppression growth. work thus presents novel approach spatiotemporal over targeted PROTAC.

Language: Английский

Citations

47
TRAP1 drives smooth muscle cell senescence and promotes atherosclerosis via HDAC3-primed histone H4 lysine 12 lactylation DOI Creative Commons
Xuesong Li, Minghong Chen,

Xiang Chen

et al.

European Heart Journal, Journal Year: 2024, Volume and Issue: 45(39), P. 4219 - 4235

Published: Aug. 1, 2024

Vascular smooth muscle cell (VSMC) senescence is crucial for the development of atherosclerosis, characterized by metabolic abnormalities. Tumour necrosis factor receptor-associated protein 1 (TRAP1), a regulator associated with ageing, might be implicated in atherosclerosis. As role TRAP1 atherosclerosis remains elusive, this study aimed to examine function VSMC and

Language: Английский

Citations

38
New-generation advanced PROTACs as potential therapeutic agents in cancer therapy DOI Creative Commons
Chao Wang, Yujing Zhang,

Wujun Chen

et al.

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: May 21, 2024

Abstract Proteolysis-targeting chimeras (PROTACs) technology has garnered significant attention over the last 10 years, representing a burgeoning therapeutic approach with potential to address pathogenic proteins that have historically posed challenges for traditional small-molecule inhibitors. PROTACs exploit endogenous E3 ubiquitin ligases facilitate degradation of interest (POIs) through ubiquitin–proteasome system (UPS) in cyclic catalytic manner. Despite recent endeavors advance utilization clinical settings, majority fail progress beyond preclinical phase drug development. There are multiple factors impeding market entry PROTACs, insufficiently precise favorable POIs standing out as one most formidable obstacles. Recently, there been exploration new-generation advanced including PROTAC prodrugs, biomacromolecule-PROTAC conjugates, and nano-PROTACs, improve vivo efficacy PROTACs. These improved possess capability mitigate undesirable physicochemical characteristics inherent thereby enhancing their targetability reducing off-target side effects. The will mark pivotal turning point realm targeted protein degradation. In this comprehensive review, we meticulously summarized state-of-the-art advancements achieved by these cutting-edge elucidated underlying design principles, deliberated upon prevailing encountered, provided an insightful outlook on future prospects within field.

Language: Английский

Citations

35
Characteristic roadmap of linker governs the rational design of PROTACs DOI Creative Commons
Yawen Dong, Tingting Ma, Ting Xu

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(10), P. 4266 - 4295

Published: April 11, 2024

Proteolysis targeting chimera (PROTAC) technology represents a groundbreaking development in drug discovery, leveraging the ubiquitin‒proteasome system to specifically degrade proteins responsible for disease. PROTAC is characterized by its unique heterobifunctional structure, which comprises two functional domains connected linker. The linker plays pivotal role determining PROTAC's biodegradative efficacy. Advanced and rationally designed linkers are under development. Nonetheless, correlation between characteristics efficacy remains under-investigated. Consequently, this study will present multidisciplinary analysis of their impact on efficacy, thereby guiding rational design linkers. We primarily discuss structural types linkers, optimization strategies used design. Furthermore, we how factors like length, group type, flexibility, linkage site affect biodegradation efficiency PROTACs. believe that work contribute towards advancement research area.

Language: Английский

Citations

30
Targeted protein degradation: advances in drug discovery and clinical practice DOI Creative Commons
Guangcai Zhong, Xiaoyu Chang, Weilin Xie

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 6, 2024

Abstract Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing stark contrast to traditional approaches like small molecule inhibitors that primarily focus on inhibiting function. This advanced technology capitalizes the cell’s intrinsic proteolytic systems, including proteasome and lysosomal pathways, selectively eliminate disease-causing proteins. TPD not only enhances efficacy of treatments but also expands scope applications. Despite its considerable potential, faces challenges related properties drugs their rational design. review thoroughly explores mechanisms clinical advancements TPD, from initial conceptualization practical implementation, with particular proteolysis-targeting chimeras molecular glues. In addition, delves into emerging technologies methodologies aimed at addressing these enhancing efficacy. We discuss significant trials highlight promising outcomes associated drugs, illustrating potential transform treatment landscape. Furthermore, considers benefits combining other therapies enhance overall effectiveness overcome drug resistance. The future directions applications are explored, presenting an optimistic perspective further innovations. By offering comprehensive overview current innovations faced, this assesses transformative revolutionizing development setting stage for new era medical therapy.

Language: Английский

Citations

29
Macrophage MCT4 inhibition activates reparative genes and protects from atherosclerosis by histone H3 lysine 18 lactylation DOI Creative Commons

Yunjia Zhang,

Hong Jiang,

Mengdie Dong

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(5), P. 114180 - 114180

Published: May 1, 2024

Macrophage activation is a hallmark of atherosclerosis, accompanied by switch in core metabolism from oxidative phosphorylation to glycolysis. The crosstalk between metabolic rewiring and histone modifications macrophages worthy further investigation. Here, we find that lactate efflux-associated monocarboxylate transporter 4 (MCT4)-mediated lactylation closely related atherosclerosis. Histone H3 lysine 18 dependent on MCT4 deficiency activated the transcription anti-inflammatory genes tricarboxylic acid cycle genes, resulting initiation local repair homeostasis. Strikingly, characteristically involved stage-specific process during M1 M2 transformation, whereas methylation acetylation are not. Gene manipulation protein hydrolysis-targeted chimerism technology used confirm favors ameliorating Therefore, our study shows macrophage deficiency, which links modifications, plays key role training become homeostasis phenotypes.

Language: Английский

Citations

28