ABSTRACT
Epigenetic mediation through bromodomain and extraterminal (BET) proteins have progressively translated protein imbalance into effective cancer treatment. Perturbation of druggable BET proteins through proteolysis-targeting chimeras (PROTACs) has recently contributed to the discovery of effective therapeutics. Unfortunately, precise and microenvironment-activatable BET protein degradation content with promising tumor selectivity and pharmacological suitability remains elusive. Here, we present an enzyme-derived clicking PROTACs (ENCTACs) capable of orthogonally cross-linking two disparate small-molecule warhead ligands that recognize BET bromodomain-containing protein 4 (BRD4) protein and E3 ligase within tumors only upon hypoxia-induced activation of nitroreductase enzyme. This localized formation of heterobifunctional degraders promotes specific down-regulation of BRD4, which subsequently alters expression of epigenetic targets and, therefore, allows precise modulation of hypoxic signaling in live cells, zebrafish, and living mice with solid tumors. Our activation-feedback system demonstrates compelling superiorities and may enable the PROTAC technology with more flexible practicality and druggable potency for precision medicine in the near future.
ABSTRACT
In situ self-assembly has attracted increasing research interest for applications in imaging and therapy in recent years. Particularly for protease-activated developments, inspiration is drawn from the innate specificity of their catalytic activities, rapid discovery of the various roles they play in the proliferation of certain diseases, and inherent susceptibility of small molecule peptide conjugates to proteolytic digestion in vivo. The overexpression of a disease-related protease of interest can be exploited as an endogenous stimulus for site-specific self-assembly to largely amplify a molecular event happening at the cellular level. This holds great potential for applications in early stage disease detection, long-term disease monitoring, and sustained therapeutic effects. This review summarizes the recent developments in protease-activated self-assemblies for imaging and therapeutic applications toward the manifestation of tumors, bacterial infections, neurodegenerative disorders, and wound recovery.
Subject(s)
Biocompatible Materials/pharmacology , Neoplasms/drug therapy , Peptide Hydrolases/metabolism , Peptides/pharmacology , Bacterial Infections/drug therapy , Bacterial Infections/metabolism , Biocompatible Materials/chemistry , Biocompatible Materials/metabolism , Humans , Materials Testing , Neoplasms/metabolism , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/metabolism , Particle Size , Peptide Hydrolases/chemistry , Peptides/chemistry , Peptides/metabolism , Wound Healing/drug effectsABSTRACT
Bacterial infection is a universal threat to public health, which not only causes many serious diseases but also exacerbates the condition of the patients of cancer, pandemic diseases, e.g., COVID-19, and so on. Antibiotic therapy has been used to be an effective way for common bacterial disinfection. However, due to the misuse and abuse of antibiotics, more and more antibiotic-resistant bacteria have emerged as fatal threats to human beings. At present, more than 700,000 patients die every year with bacterial infections because of the lack of effective treatment. It is frustrating that the pace of development of antibiotics lags far behind that of bacterial resistance, with an estimation of 10 million deaths per year from bacterial infections after 2050. Facing such a rigorous challenge, approaches for bacterial disinfection are urgently demanded. The recently developed near-infrared (NIR) light-irradiation-based bacterial disinfection is highly promising to shatter bacterial resistance by employing NIR light-responsive materials as mediums to generate antibacterial factors such as heat, reactive oxygen species (ROS), and so on. This treatment approach is proved to be a potent candidate to accurately realize spatiotemporal control, while effectively eradicating multidrug-resistant bacteria and inhibiting antibiotic resistance. Herein, we summarize the latest progress of NIR light-based bacterial disinfection. Ultimately, current challenges and perspectives in this field are discussed.
