Dengue is the most common global problem in recent times, particularly in tropical and subtropical areas, yet antivirals for therapy or prophylaxis are lacking. Millions of people are affected by this dengue virus, but no proper medication is available yet to cure this disease. One polyprotein that is encoded by the DENV genome is converted into structural and non-structural proteins that are necessary for viral pathogenesis and replication. Among these, the non-structural protein complex NS2B-NS3 is essential for viral polyprotein processing, replication, and host innate immune response control. It acts as a trypsin-like serine protease. The NS2B/NS3 protease is a key enzyme involved in viral replication and serves as a major target for drug development against the dengue virus. The NS3 protease has a conserved catalytic triad (His-Asp-Ser), whereas NS2B serves as an essential cofactor that stabilizes the active conformation of the enzyme and aids in substrate recognition. By disrupting interferon signalling pathways, the NS2B-NS3 protease not only aids in viral replication but also makes immune evasion easier. The compound that inhibits the action of this enzyme could be pioneering in the antiviral drug discovery process. This article provides a comprehensive overview of the detailed structural information of the viral protease (NS2B/NS3) enzyme with the mechanistic role of this enzyme, and highlights various inhibitors related to the NS2B/NS3 protease. A more thorough comprehension of this protease could facilitate the logical development of potent antiviral medications to prevent dengue infection.
Hydroxyl radicals (•OH) are the predominant oxidative species in living systems and are associated with various diseases and physiological disorders. Because of its extremely short lifetime and inherently low steady-state concentration, real-time detection of •OH in environmental and biological systems remains highly challenging, despite its critical regulatory function. In the present study, we report the design and successful synthesis of a novel dual-channel fluorescent probe, HR-YT, for sensitive •OH monitoring. The probe exhibits a fast response along with excellent sensitivity, achieving a detection limit as low as 28 nM. Importantly, owing to its low cytotoxicity, HR-YT is also suitable for detecting exogenous •OH in living cells, plant tissues, and zebrafish models. Furthermore, probe HR-YT has been used to screen the non-tumor macrophage cells from selected tumor cells when stimulated with β-Lapachone, demonstrating its potential applications in biological imaging.
Netrin-1 is a secreted glycoprotein that is overexpressed in non-small cell lung cancer (NSCLC) and breast cancer, making it an emerging biomarker for tumor diagnosis and targeted therapy. However, noninvasive imaging tools for quantitative assessment of Netrin-1 expression remain limited. In this study, leveraging the crystal structure of the Netrin-1/DCC complex, we rationally designed two Netrin-1-targeted peptides YP8 and LE7, through systematic in silico molecular docking, alanine scanning, and virtual amino acid mutation. Their corresponding 68Ga-labeled PET tracers [68Ga]Ga-NOTA-YP8 and [68Ga]Ga-NOTA-LE7, were subsequently developed. Comparative evaluation revealed that [68Ga]Ga-NOTA-LE7 exhibited superior Netrin-1 binding affinity, enhanced in vivo stability, and significantly improved tumor-to-background ratio. PET imaging demonstrated specific and robust uptake of [68Ga]Ga-NOTA-LE7 in Netrin-1-positive A549 and 4T1 tumors, with minimal accumulation in Netrin-1-low MDA-MB-231 tumors. The NIRF probe ICG-LE7 further confirmed specific tumor targeting and enabled fluorescence-guided surgical resection. Collectively, these findings establish [68Ga]Ga-NOTA-LE7 and ICG-LE7 as promising noninvasive diagnostic tools for Netrin-1 expression imaging.
Novel push-pull conjugated molecules combining styrylquinoline and dioxaborinine units, as well as their β-dicarbonyl precursors were designed, synthesized and tested as multitarget theranostic agents against AD with promising results. In vitro experiments demonstrated favorable fluorescent properties for optical imaging; histological studies proved their excellent performance as selective amyloid-targeted optical probes and preliminary in vivo experiments confirmed their suitability as diagnostic agents for fluorescence imaging in AD mice with an intact skull, without the need of opening a cranial window. In terms of their therapeutic potential, in vitro experiments showed a good antiaggregating activity towards the two misfolded proteins involved in AD, amyloid β and tau protein. Overall, these compounds, and particularly the dioxaborinine derivatives, are promising multitarget theranostic candidates against Alzheimer's disease.
PANoptosis, a combination of apoptosis, pyroptosis, and necroptosis, plays a key role in the occurrence and development of tumors. In this article, a series of benzimidazole-carbazole-based compounds were developed, which exhibited broad cytotoxicity against eight different cancer cell lines, with significant activity against HepG2 cells. Among them, 3m shows the strongest antiproliferative by preventing HepG2 cells in the G2/M stage. Moreover, 3m can effectively inhibit cell colony formation and migration. Mechanistically, 3m induce PANoptosis in HepG2 cells by upregulating of NLRP3, BAX/BCL2, and cleaved caspase3 expressions, along with the cleavage of gasdermin E (GSDME) into its N-terminal fragment (GSDME-N) and increasing phosphorylation level of MLKL. Additionally, 3m responds to pH/Viscosity. The present study describes a novel therapeutic 3m for the treatment of cancer, providing valuable insights into understanding the anticancer properties of these compounds.
