ACS Pharmacology and Translational Science最新文献

Pseudomonas aeruginosa is considered one of the most threatening pathogens worldwide, due to its high adaptability, which leads to resistance to classical antimicrobials. This fact has driven the development of new therapeutic strategies to reduce multiresistant strains and to minimize infection progression. In this context, the protective effect of a monoclonal antibody (mAb122) specific to pyocyanin (PYO), a key virulence factor of P. aeruginosa, was studied in vitro. Quenching PYO may reduce P. aeruginosa pathogenesis and partially lessen host immune dysregulation by impairing cytokine production. With this aim, murine macrophages were challenged with different PYO concentrations to assess their cytotoxicity by evaluating different cell viability hallmarks. Subsequently, the protective effect of mAb122 was studied on the PYO-treated cells. The addition of mAb122 significantly increased the percentage of viable cells compared to those treated just with the virulence factor (4.34- to 11.07-fold increase in MH-S and RAW 264.7 cells, respectively). Moreover, the PYO immunomodulatory effect and the outcome of mAb122 addition on the host response were also studied by measuring relevant cytokines in cell media. Results showed that mAb122 treatment, rather than reversing PYO impairment in cytokine production, either maintained the levels or triggered an increase, depending on the specific cytokine examined. Thus, the significant rise in cell viability and the nontoxic effect of mAb122 itself in vitro place PYO mAb as a promising candidate for in vivo testing as a potential therapeutic agent. However, its effects on the host immune system should be carefully studied and minimized.

Fragile X-associated tremor/ataxia syndrome (FXTAS), a nucleotide repeat expansion disorder, arises from CGG repeat expansions in the 5′ untranslated region (UTR) of the fragile X messenger ribonucleoprotein 1 (FMR1) gene, leading to RNA foci formation and toxic protein aggregation via repeat-associated non-AUG (RAN) translation. These fundamental mechanisms often lead to a series of consequences, including splicing defects, neuroinflammation, mitochondrial dysfunction, impaired autophagy, and cell death. Targeting toxic RNA repeats offers a promising therapeutic strategy. In this study, we identified Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, as a potential treatment for FXTAS. At first, we utilized various biophysical assays and molecular docking to confirm Celecoxib’s strong binding affinity toward the r(CGG)_exp RNA. Further studies in the cellular model demonstrated the potency of Celecoxib in reducing toxic protein aggregates and improving splicing defects. Notably, it significantly reduces FMR1PolyG aggregates in the Drosophila FXTAS model, leading to improved locomotor impairments and the mitigation of associated downstream pathological consequences. Moreover, Celecoxib treatment significantly extends the lifespan of the flies. Thus, these results collectively support the therapeutic potential of repurposing Celecoxib for the treatment of FXTAS.

Thrombotic diseases, classified as arterial or venous, remain one of the most important global health concerns. Myocardial infarction, ischemic stroke, and venous thromboembolism (VTE), which include deep vein thrombosis and pulmonary embolism, are prominent causes of illness and death. Antithrombotic agents, classified by their sites of action, are essential for preventing and treating thrombus formation. Transdermal drug delivery systems have emerged as promising alternatives for antithrombotic therapy by improving drug bioavailability, patient adherence, and therapeutic efficacy while reducing side effects. This systematic review, conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, identified 25 relevant articles through structured database searches. An additional search in clinical trial registries revealed no ongoing or completed clinical studies involving transdermal antithrombotic therapy. The literature focuses on transdermal formulations of heparins and acetylsalicylic acid, with fewer reports on direct oral anticoagulants and other agents. The literature search revealed that the most investigated delivery systems were microneedles (13), micro/nanoemulsions (2), ethosomes (1), hydrogels (5), polymeric patches (3), and liposomes (1). The ongoing interest in antithrombotic transdermal formulations highlights both their therapeutic importance and the difficulties still associated with traditional administration methods. While innovative transdermal formulations show promise, further research is necessary to develop scalable, effective, and cost-efficient technologies for clinical applications.

The Lands cycle is a fundamental process for the continuous renewal of phospholipids in cell membranes, directly influencing their fluidity and functionality. This cycle is particularly active in tissues such as the nervous and immune systems and is crucial for cellular homeostasis. It is implicated in the development of inflammatory, neurodegenerative, and cancerous diseases. The present review discusses the biochemical regulation of the Lands cycle─focusing on phospholipase A2 (PLA₂) and lysophospholipid acyltransferase (LPCAT)─and its impact on lipid metabolism, cell signaling, and disease. Dysregulation of this cycle has been linked to pathological conditions, including oncogenesis and hepatotoxicity. This suggests that modulation of the cycle may have an effect on inflammatory responses and tumor resistance. Advances in the fields of lipidomics and computational modeling have resulted in a more comprehensive understanding of the Lands cycle, thereby emphasizing its potential as a therapeutic target.

Overactive epidermal growth factor receptor (EGFR) signaling is often involved in driving different types of carcinomas. It is a well-studied target for targeted therapies, with both monoclonal antibodies and kinase inhibitors available for clinical use. Even though these drugs show a clinical benefit, most patients develop resistance over time. The development of new therapeutic modalities is therefore highly motivated. Herein, we describe a new type of drug candidate targeting EGFR, a so-called affibody-based drug conjugate. It consists of an EGFR-targeting affibody molecule, Z_EGFR, expressed as a fusion to an albumin-binding domain for half-life extension, and coupled with the potent cytotoxic drug DM1 via a maleimidocaproyl linker. The resulting drug conjugate Z_EGFR-ABD-mcDM1, showed strong binding to recombinant EGFR and EGFR-expressing cells. It was found to be highly potent in killing EGFR-expressing A431 cells with an IC₅₀ of 3.4 nM. In vivo, it showed moderate uptake in A431-derived xenografts with high EGFR expression. Collectively, the results from this study, demonstrate a potent and EGFR-specific drug candidate that holds promise for further development.

Screening diverse chemical structure compounds is an essential task in modern drug discovery. It provides different opportunities to avoid patent invasion, avoid potential toxicity observed in similar compounds, and execute new potential pharmacological functions. G protein-coupled receptors (GPCRs) span an important family of membrane proteins that play a central role in signal transduction and serve as significant drug targets. A prototypical class A GPCR is the β₂-adrenergic receptor (β₂AR), which is widely targeted by agonists to treat respiratory diseases. Although various β₂AR agonists are currently available on the market, there is still an urgent demand for further optimizing drug safety, efficacy, and selectivity. Here, we combine machine learning (ML) methods with other computational methods to efficiently screen agonists against β₂AR from a large compound library, composited of 19 million molecules. Verified by cellular functional assays, we identified several extremely potent agonists showing EC₅₀ values in the range of 0.2–20 nM with new chemical structures, of which the structure is diverse from previous reported molecules. Our machine learning computational approaches provide new possibilities to design novel drug candidates for GPCR.

Hypertension is a major cardiovascular risk factor that perturbs neurohumoral regulation, yet its integrated effects on circadian sleep–wake organization and neurocardiac coupling remain unclear. We examined whether the severity of hypertension induces internal circadian misalignment and neurocardiac desynchronization. Male Wistar rats were assigned to the control, high-fructose (HF; mild hypertension), and DOCA-salt (severe hypertension) groups. Across 24 h, we evaluated neurohumoral markers (melatonin, norepinephrine, angiotensin II, vasopressin, and corticosterone), calcium, cardiovascular function (blood pressure, ECG, HRV, and echocardiography), sleep–wake behavior (EEG/EMG), and molecular oscillations of Bmal1, Per1, CACNA1C, and ANP in the SCN and heart. Temporal allostatic load and causal network inference were applied to assess the systemic strain. Both hypertensive models established new blood pressure set points, with HF rats stabilizing at mild hypertension levels and DOCA-salt rats stabilizing at severe hypertension levels. Both exhibited increased neurohumoral load, autonomic imbalance, and ECG/HRV alterations, while DOCA-salt rats showed marked melatonin suppression, sustained elevations of norepinephrine, AVP, corticosterone, and calcium and pronounced NREM–REM fragmentation. Cardiac Bmal1 and Per1 were phase-shifted, CACNA1C was upregulated, and ANP was downregulated, while SCN rhythms were preserved, indicating peripheral desynchronization. Allostatic load analysis revealed an early and persistent burden in DOCA-salt rats and delayed but significant increases in HF rats. Causal network modeling demonstrated a progressive loss of melatonin’s upstream regulation, replaced by neurohumoral dominance, indicating potential pathways in the treatment of hypertension-induced sleep–wake disturbances. These findings indicate that the severity of hypertension reorganizes systemic temporal architecture, amplifying circadian misalignment and SCN–heart decoupling, highlighting the need for stage-specific chronotherapeutic strategies.

The primary goal of antiplatelet therapy is to inhibit platelet aggregation without increasing the risk of bleeding. Treatment resistance and recurrence of thrombotic events are common, underscoring the need to identify new molecules with antiplatelet activity. In this research, we synthesized and characterized spiro-hydroquinone derivatives substituted with various aliphatic chain lengths (1–9 carbons) and evaluated the effect of these modifications on platelet activation. The structure–activity relationship study revealed that increasing the aliphatic chain length did not enhance antiplatelet activity; instead, it increased cytotoxicity and negatively affected solubility. Notably, the shortest molecule, SD3A, inhibits mitochondrial function and acts selectively on collagen-mediated activation, resulting in reduced thrombus formation without affecting coagulation, thereby representing a low risk of bleeding in vitro. These results identify ortho-carbonylhydroquinone spiro derivatives, specifically SD3A, as a promising antiplatelet molecule, demonstrating an optimal combination of low cytotoxicity and pathway-selective activity against collagen.

Nociceptive pain, resulting from tissue injury or inflammation, affects a large portion of the global population. This type of pain is commonly treated by small molecules that are associated with a variety of drawbacks, including addiction and potential liver or kidney damage, highlighting the need for new therapeutic strategies. Here, we report the design, synthesis, and characterization of EG01449 (12h), a quinoline-based neuropilin-1 (NRP1) antagonist with analgesic effects in vascular endothelial growth factor (VEGF)-induced pain models. Neuropilin-1 is a critical coreceptor mediating VEGF signaling. In models of VEGF-induced pain, the VEGFA₁₆₅a isoform increases currents through voltage-gated sodium and calcium channels in dorsal root ganglia sensory neurons. Notably, this effect was mitigated upon the inhibition of NRP1 by 12h, while 12h alone showed no discernible impact on sodium currents. Compound 12h also attenuated sensitivity to mechanical stimuli and cold-induced allodynia. Unlike the previously reported NRP1-targeting compounds that may activate intracellular signaling, 12h did not activate p38 mitogen-activated protein kinase and exhibited a purely inhibitory pharmacological profile. Structural comparison using X-ray crystallography revealed an additional hydrogen bond that contributes to the increased stabilization of the 12h/NRP1 complex. These findings demonstrate that the NRP1 inhibitor 12h elicits an antinociceptive effect and highlight the impact of subtle structural modifications on biological outcomes. NRP1 antagonism thus represents a promising new modality for the treatment of chronic pain conditions.