Search Results (93)

Carbapenem-resistant Acinetobacter baumannii (CRAB) is classified by the World Health Organization among the critical-priority pathogens, reflecting high mortality, near-ubiquitous nosocomial spread, and a depleted therapeutic pipeline. No antibiotic chemical class with a genuinely novel target and activity against A. baumannii reached patients for more than fifty years, and current options—sulbactam–durlobactam, cefiderocol, polymyxins, high-dose ampicillin–sulbactam and tetracyclines—are constrained by toxicity, inconsistent efficacy, or emerging resistance. Against this background, zosurabalpin (RG6006), the first member of the tethered macrocyclic peptide (MCP) class, represents a potentially important conceptual advance. Identified through whole-cell phenotypic screening of nearly 45,000 macrocyclic peptides and optimized into a zwitterionic clinical candidate, zosurabalpin inhibits the LptB₂FGC complex, the inner-membrane ATP-binding-cassette transporter that initiates lipopolysaccharide (LPS) export. By trapping LPS within the transporter, the drug causes lethal accumulation of the molecule at the inner membrane. This mechanism is structurally distinct from that of every clinically used antibiotic and, in preclinical studies, is not affected by the major currently recognized CRAB resistance mechanisms. Zosurabalpin shows potent, narrow-spectrum activity essentially restricted to the Acinetobacter baumannii–calcoaceticus complex, retaining activity in vitro against isolates resistant to cefiderocol and last-line agents; its clinical efficacy in patients, however, remains to be established. Here we review the discovery, structural mechanism, microbiological spectrum, and clinical development of zosurabalpin, and we situate it within a broader revival of pathogen-specific (narrow-spectrum) antibiotic development, discussing the diagnostic, stewardship, and economic implications of this paradigm. Full article

Selective inhibition of the tumour-associated carbonic anhydrase (CA) isoforms IX and XII, which are overexpressed in hypoxic tumours, has emerged as a promising strategy for the development of novel anticancer agents. Among the diverse CA inhibitors reported to date, coumarins have attracted particular attention. These chromenone derivatives, widely distributed in phytochemicals, display a broad range of biological activities and are known to act as suicide inhibitors of CAs. Following the tail approach, we designed a series of hybrid compounds combining a coumarin core with an N-arylthioureido scaffold located at the C-7 position and investigated how structural variations—including substituents on the coumarin and aromatic moieties, tether length, and urea/thiourea isosterism—influence their biological properties (CA inhibition and antiproliferative activity). Substituted coumarins at C-3 and C-4 were efficiently prepared via Pechmann condensation, while the thioureido motif was introduced using various aryl isothiocyanates as key synthetic intermediates. The lead compound, featuring a dimethylated coumarin, a pentyl linker, and an N-(p-tolyl)thioureido residue, inhibited the target enzymes in the low- to mid-nanomolar range (K_i = 6.0 and 49.9 nM, respectively), displaying selectivity indexes (S.I.s) surpassing those of the reference drug acetazolamide (AAZ). Moreover, it exhibited potent antiproliferative activity, with GI₅₀ values in the low micromolar range (1.9–3.5 µM) against both drug-sensitive and multidrug-resistant cancer cell lines. Label-free three-dimensional holotomographic microscopy revealed that this compound triggers slow apoptosis, leading to cell death after approximately 20 h of exposure. Full article

G protein-coupled receptor kinase 5 (GRK5) is an important therapeutic target involving cardiovascular diseases, cancer, and inflammatory disorders. However, the features of its activation as an essential function regulation process have been poorly understood, limiting related drug development. The work utilizes a molecular dynamics simulation coupled with an interpretable machine learning model to identify key structure and dynamics determinants distinguishing the active and inactive states of GRK5. Benefiting from the unbiased and data-driven framework, the work reveals that the active site tether (AST) is a dominant activation-associated feature, acting as a conformational switch that regulates kinase domain movements. Beyond this canonical element, we also uncover two previously underappreciated structure modules contributing to GRK5 activation, such as the coupling interaction between the α10/α11 helix interface with the N-terminal lipid-binding domain (NLBD) in the active state, and the α5 helix region that facilitates large-scale RH domain reorientation. Conformation dynamics analyses further indicate that GRK5 activation involves disruption of the interdomain interactions and interaction coupling between AST, αN-helix, kinase domain N-lobe, NLBD, and α10/α11 hinge. These observations provide valuable insights into understanding the GPK5 activation mechanism and also highlight the power of machine learning in capturing functionally conformational changes, and in turn offering a methodological guideline for the studying of the protein function mechanism. Full article

Background: The potent topoisomerase I inhibitor SN-38, the active metabolite of irinotecan, is limited in clinical application due to severe systemic toxicity. Prodrug strategies enabling selective activation in the tumor microenvironment offer a promising approach to improve its therapeutic index. This study aims to rationally design, synthesize, and systematically evaluate novel disulfide-based SN-38 prodrugs engineered for redox-responsive activation in hypoxic tumors. Methods: Two novel disulfide-based SN-38 prodrugs (SN-38-CSS and SN-38-LSS) were designed and synthesized; SN-38-CSS incorporates a constrained cis-piperazine-fused six-membered cyclic disulfide linker, while SN-38-LSS contains a linear disulfide tether, to differentially exploit the upregulated thioredoxin (Trx/TrxR) system in hypoxic tumor microenvironments. Results: Both prodrugs demonstrated high stability under physiological pH conditions and in human plasma, minimizing premature release. Crucially, they exhibited selective, rapid degradation in the presence of dithiol reductants (TCEP and DTT), mimicking Trx system activity, while remaining stable towards monothiols (GSH, L-Cys). In vitro cytotoxicity assays revealed that the prodrugs exhibited significantly reduced toxicity compared to SN-38 under normoxic conditions across most tested cell lines. However, under hypoxic conditions, their activity was significantly restored. Specifically, SN-38-CSS exhibited cytotoxicity comparable to SN-38 against MCF-7 and NCI-N87 cells, whereas SN-38-LSS showed lower activation efficiency. Conclusions: SN-38-CSS is identified as a promising redox and hypoxia dual-responsive prodrug candidate, highlighting the strategic use of cyclic disulfide linkers for achieving high selectivity and controlled drug release within the tumor microenvironment. Full article

Background: Inhibition of histone deacetylase is a highly sought-after objective in the fight against cancer. Thus, the development of innovative HDAC inhibitors with significantly higher potency than SAHA against specific cancer cell types represents complex and demanding work. Method: The utilization of the underexplored and privileged scaffold 4-chlorothieno[2,3-b]pyridine as a cap tethering diverse aliphatic and aromatic linkers, followed by the screening of both cellular and enzymatic activities, is undertaken in this study. Results: Compounds 7a and 9a demonstrated impressive mean GI₅₀ values of 2.15 µM and 1.89 µM, respectively. Both compounds reduced caspase-3 levels in RPMI-8226 cells, suggesting induction of apoptosis. Compound 7a showed remarkable IC₅₀ values of 0.37 µM, 0.58 µM, and 0.70 µM against HDACs 1, 4, and 6, respectively, consistent with the cellular assay. Additionally, compound 7a exhibited a selectivity index of 11 for RPMI-8226 cells over PBMCs, reflecting its high selectivity and potential safety. Moreover, ADMET prediction tools indicated that compounds 7a and 9b may have more favorable pharmacokinetic properties than the gold-standard HDAC inhibitor, SAHA. Conclusions: Further study and exploration of the derivatives of compounds 7a and 9a can lead to further advancement in the development of potent HDAC inhibitor anticancer drugs. Full article

The development of biohybrid micro-robots represents a groundbreaking advancement in targeted drug delivery for cancer therapy, offering unprecedented precision and reduced systemic toxicity. These microscale robots integrate synthetic materials with biological components such as bacteria, algae, red blood cells, or spermatozoa, capitalizing on the inherent motility, biocompatibility, and targeting capabilities of living organisms. This hybridization enables active navigation through complex biological environments, overcoming physiological barriers such as the blood–brain and endothelial junctions that impede traditional nanoparticle-based systems. In this study, we propose a multi-functional biohybrid micro-robotic platform composed of magnetically actuated synthetic chassis coated with doxorubicin-loaded lipid vesicles and tethered to Magnetospirillum magneticum for propulsion and tumor-homing capabilities. The results underscore the promise of biohybrid micro-robots as intelligent, minimally invasive agents for next-generation oncological therapies, capable of delivering chemotherapeutics with enhanced spatial and temporal accuracy. Future work will focus on clinical translation pathways, biosafety evaluations, and scalability of production under Good Manufacturing Practice (GMP) standards. Full article

The adhesion G protein-coupled receptor ADGRE5/CD97 is upregulated in many cancers, representing a potential drug target in oncology/immuno-oncology. Yet, ADGRE5′s activation and signaling mechanisms remain poorly understood. Here, we used enhanced bystander bioluminescence resonance energy transfer (ebBRET)-based biosensors and three strategies to characterize human (h) ADGRE5 signaling. First, a synthetic tobacco etch virus (TEV) protease-cleavable receptor chimera enabling controlled tethered agonist (TA) exposure at the GPCR proteolysis site (GPS) revealed signaling through Gα12 and Gα13, along with the recruitment of β-Arrestins 1/2 (β-Arrs). Second, we investigated WT hADGRE5 signaling elicited by Gingipain K (Kgp), an endopeptidase that cleaves hADGRE5 upstream of the GAIN domain. Kgp mirrored TEV-induced signaling but also promoted Gαz and Gα11 activity. The abolition of hADGRE5′s GPS did not block Kgp-induced receptor activation, revealing a GPS cleavage-independent mechanism of action. Finally, we developed an assay to study hADGRE5 mechanical stimulation (MS) using β-Arr2 as a readout. MS promoted β-Arr2 recruitment in hADGRE5-expressing cells, and this response was lost upon abolition of the GPS. A neutralizing antibody to the hADGRE5 ligand CD55 significantly dampened MS-induced β-Arr2 engagement. Overall, this study advances our understanding of hADGRE5′s signaling and highlights the receptor’s plasticity in activating pathways via both GPS cleavage-dependent and -independent mechanisms. Full article

Targeted degradation technologies, primarily referring to targeted protein degradation, have emerged as promising drug discovery strategies. In contrast to traditional “occupancy-driven” inhibition approaches, these technologies ingeniously leverage the cell’s endogenous degradation mechanisms to achieve specific elimination of disease-causing targets. Autophagy, a highly conserved cellular clearance pathway, possesses broad substrate recognition capabilities, enabling degradation of not only individual proteins but also protein aggregates, damaged organelles, and invading pathogens. Given these characteristics, researchers are actively exploring the application of autophagy mechanisms in targeted degradation technologies. Herein, we summarize recent advances in autophagy-dependent degradation approaches, including autophagosome tethering compounds (ATTEC), autophagy-targeting chimeras (AUTAC), autophagy-targeting Chimera (AUTOTAC), chaperone-mediated autophagy (CMA)-based methods, nanotechnology-based strategies, and the newly introduced autophagy-induced antibody (AUTAB) technique, highlighting their mechanisms, advantages, and potential applications in treating tumors, neurodegenerative diseases, and other challenging conditions. Full article

The management of nasopharyngeal cancer (NPC) is rapidly evolving, with immune checkpoint inhibitors emerging as a prominent treatment approach. However, drug development targeting specific molecular and cellular abnormalities in NPC has slowed. Recent advancements in artificial intelligence (AI) and bioinformatics, particularly those integrating multi-omics data, offer a more effective alternative to traditional in vitro screening methods for identifying clinically actionable targets in NPC. Through a combination of multi-omics analyses and AI-driven screening, we identified CACNA2D1 as a novel cancer-cell-specific therapeutic target in NPC. Our research indicates that exploiting Epstein–Barr virus (EBV) tethering increases H3K27 acetylation near the CACNA2D1 promoter. Analysis of clinical specimens revealed significant upregulation of CACNA2D1 at both the transcriptional and translational levels (p-value < 0.01). Functional studies demonstrated that the mouse tumour size shrank by one-third upon the depletion of CACNA2D1, and there was an 85% reduction in cancer cell growth through the blockage of enhancers, while the presence of CACNA2D1 conferred a survival advantage during NPC tumour development. These findings highlight the potential of CACNA2D1 as a promising target for therapeutic intervention in NPC. Full article

Background: Despite recent breakthroughs in cancer treatment, non-small cell lung cancer (NSCLC) and breast cancer remain major causes of death from all malignancies. The epidermal growth factor receptor (EGFR) is an important mediator of the pathways involved in cell proliferation, apoptosis, and angiogenesis. Thus, its overexpression triggers several types of cancer, including NSCLC and breast cancer. Methods: In the current study, we synthesized new pyrimidine-tethered compounds (chalcone derivative (B-4), pyrazoline–carbothioamide (B-9), and pyrazoline–thiazole hybrids (BH1-7)). These compounds were then tested for cytotoxicity against A549 NSCLC and MCF-7 breast cancer cells. Results: Of these, B-4 displayed significant cytotoxicity against both cells (IC₅₀ = 6.70 ± 1.02 µM for MCF-7; IC₅₀ = 20.49 ± 2.7 µM for A549) compared to the standard agent lapatinib (IC₅₀ = 9.71 ± 1.12 µM for MCF-7; IC₅₀ = 18.21 ± 3.25 µM for A549). The anticancer potential of B-4 between Jurkat leukemic T cells and peripheral blood mononuclear cells (PBMCs) (healthy) was found to be selective. Mechanistically, 11.9% and 10.2% of A549 and MCF-7 cells treated with B-4, respectively, underwent apoptosis and B-4 produced 46% EGFR inhibition at a concentration of 10 μM. The B-4/EGFR complex obtained after induced fit docking was subjected to 300 ns of molecular dynamics simulation, which confirmed the stability of the complex in a mimicked biological environment. On the other hand, B-4 was shown to have drug-like properties by in silico pharmacokinetic estimation. Conclusions: B-4 is an EGFR inhibitor and apoptosis inducer for future NSCLC and breast cancer studies. Full article

The lens epithelium derived growth factor of 75 kD (LEDGF/p75) is a transcription co-activator and epigenetic reader that has emerged as a stress oncoprotein in multiple human cancers. Growing evidence indicates that it promotes tumor cell survival against certain therapeutic drugs. The amino (N)-terminal region of LEDGF/p75 contains a PWWP domain that reads methylated histone marks, critical for recognizing transcriptionally active chromatin sites. Its carboxyl (C)-terminus has an integrase binding domain (IBD) that serves as the binding site for the HIV-1 integrase and multiple oncogenic transcription factors. Acting as hubs for protein-protein interactions, both domains facilitate the tethering of oncogenic transcription factors and regulators to active chromatin to regulate mRNA splicing, promote DNA repair, and enhance the expression of stress and cancer-related genes that contribute to tumor cell aggressiveness and chemoresistance. This review summarizes our current knowledge of the emerging roles of LEDGF/p75 in cancer biology and therapy resistance and discusses its potential as a novel oncotherapeutic target in combinatorial treatments. Full article

Inhibition of multiple cancer-related pathways has made niclosamide a promising candidate for the treatment of various cancers. However, its clinical application has been significantly limited by poor bioavailability. This review will discuss current findings on improving niclosamide bioavailability through modification of its chemical structure and utilization of novel nanotechnologies, like electrospraying and supercritical fluids, to improve drug delivery. For example, niclosamide derivatives, such as o-alkylamino-tethered niclosamide derivates, niclosamide ethanolamine salt, and niclosamide piperazine salt, have demonstrated increased water solubility without compromising anticancer activity in vitro. Additionally, this review briefly discusses recent findings on the first pass metabolism of niclosamide in vivo, the role of cytochrome P450-mediated hydroxylation, UDP-glucuronosyltransferase mediated glucuronidation, and how enzymatic inhibition could enhance niclosamide bioavailability. Ultimately, there is a need for researchers to synthesize, evaluate, and improve upon niclosamide derivatives while experimenting with the employment of nanotechnologies, such as targeted delivery and nanoparticle modification, as a way to improve drug administration. Researchers should strive to improve drug-target accuracy, its therapeutic index, and increase the drug’s efficacy as an anti-neoplastic agent. Full article

Multitarget compounds have emerged as promising drug candidates to cope with complex multifactorial diseases, like Alzheimer’s disease (AD). Most multitarget compounds are designed by linking two pharmacophores through a tether chain (linked hybrids), which results in rather large molecules that are particularly useful to hit targets with large binding cavities, but at the expense of suffering from suboptimal physicochemical/pharmacokinetic properties. Molecular size reduction by removal of superfluous structural elements while retaining the key pharmacophoric motifs may represent a compromise solution to achieve both multitargeting and favorable physicochemical/PK properties. Here, we report the stepwise structural simplification of the dihydroxyanthraquinone moiety of a rhein–huprine hybrid lead by hydroxy group removal—ring contraction—ring opening—ring removal, which has led to new analogs that retain or surpass the potency of the lead on its multiple AD targets while exhibiting more favorable drug metabolism and pharmacokinetic (DMPK) properties and safety profile. In particular, the most simplified acetophenone analog displays dual nanomolar inhibition of human acetylcholinesterase and butyrylcholinesterase (IC₅₀ = 6 nM and 13 nM, respectively), moderately potent inhibition of human BACE-1 (48% inhibition at 15 µM) and Aβ42 and tau aggregation (73% and 68% inhibition, respectively, at 10 µM), favorable in vitro brain permeation, higher aqueous solubility (18 µM) and plasma stability (100/96/86% remaining in human/mouse/rat plasma after 6 h incubation), and lower acute toxicity in a model organism (zebrafish embryos; LC₅₀ >> 100 µM) than the initial lead, thereby confirming the successful lead optimization by structural simplification. Full article

The incorporation of amide groups into biologically active molecules has been proven to be an efficient strategy for drug design and discovery. In this study, we present a simple and practical method for the synthesis of amide-containing quinazolin-4(3H)-ones under transition-metal-free conditions. This is achieved through a carbamoyl-radical-triggered cascade cyclization of N3-alkenyl-tethered quinazolinones. Notably, the carbamoyl radical is generated in situ from the oxidative decarboxylative process of oxamic acids in the presence of (NH₄)₂S₂O₈. Full article

Serine proteases regulate cell functions through G protein-coupled protease-activated receptors (PARs). Cleavage of one peptide bond of the receptor amino terminus results in the formation of a new N-terminus (“tethered ligand”) that can specifically interact with the second extracellular loop of the PAR receptor and activate it. Activation of PAR1 by thrombin (canonical agonist) and activated protein C (APC, noncanonical agonist) was described as a biased agonism. Here, we have supposed that synthetic peptide analogs to the PAR1 tethered ligand liberated by APC could have neuroprotective effects like APC. To verify this hypothesis, a model of the ischemic brain impairment based on glutamate (Glu) excitotoxicity in primary neuronal cultures of neonatal rats has been used. It was shown that the nanopeptide NPNDKYEPF-NH2 (AP9) effectively reduced the neuronal death induced by Glu. The influence of AP9 on cell survival was comparable to that of APC. Both APC and AP9 reduced the dysregulation of intracellular calcium homeostasis in cultured neurons induced by excitotoxic Glu (100 µM) or NMDA (200 µM) concentrations. PAR1 agonist synthetic peptides might be noncanonical PAR1 agonists and a basis for novel neuroprotective drugs for disorders related to Glu excitotoxicity such as brain ischemia, trauma and some neurodegenerative diseases. Full article