ACS Pharmacology and Translational Science最新文献

The accumulation of CAG nucleotide duplicates in the huntingtin (HTT) gene triggers a neurological ailment described as Huntington’s disease (HD), which is an irreversible, progressive, and inherited condition and affects both motor and cognitive abilities, resulting in a range of symptoms, including irregular gestures (chorea, dyskinesia), psychological disorders, and advanced dementia. Agomelatine is a novel antidepressant and melatonin analog. It exerts a synergistic pharmacological mechanism, combining stimulation of both MT1/MT2 melatonergic receptors with inhibition of 5-HT2C receptors. It was evaluated for its potential neuroprotective impact against HD triggered by 3-nitropropionic acid (3-NP) in rats. Four groups were established using a total of 40 rats: Group I (CTRL), Group II (AGO), Group III (3-NP), and Group IV (AGO + 3-NP). Deficits in motor function provoked by 3-NP were alleviated by agomelatine, as evidenced by increased ambulation and rearing frequencies, alongside a notable decline in immobility time of the open field assessment, elevated final falloff time of the rotarod assessment, and improved grip strength. Agomelatine also improved synaptic plasticity and neuronal survival by optimizing the expression and activity of the BDNF/TrKB/PI3K/AKT pathway and inhibiting apoptosis, microglial, and astrocytic activation. Furthermore, agomelatine administration reduced the expression of ROCK1, suppressing the release of inflammatory responses. Finally, agomelatine possessed neuroprotective activity, as proved by enhancing motor activity and histopathological abnormalities via improving the BDNF/TrKB/PI3K/AKT survival cascade and suppressing the ROCK1 inflammatory pathway.

Serotonin is a monoamine neurotransmitter, which plays an important role in the development and functioning of the central nervous system. Recent biophysical studies reveal that nonspecific interactions between serotonin and lipid membranes significantly alter lipid bilayer properties, impacting synaptic function and plasticity. To better understand these critical interactions and their broader implications for neural function and pharmacology, we investigated the interactions of serotonin (at concentrations ranging from 1 to 40 mM) with model membranes prepared as droplet interface bilayers, liposomes, and supported bilayers. These membrane systems comprised single, binary, and ternary lipid mixtures, including pure DOPC, DOPC/DOPS (10:1 mol ratio), and DOPC/Sphingomyelin/Cholesterol (1:1:0.2 mol ratio). Our analysis employing various experimental techniques shows that the interaction of serotonin with lipid membranes of diverse compositions has overall nonspecific effects in (1) influencing the barrier properties of the lipid membrane, as demonstrated by increased water permeability compared to the control; (2) modifying the phase transition behavior, evidenced by decrease in the main phase transition temperature and reduction of the transition enthalpy; (3) perturbing the conformational ordering of lipid membranes, as indicated by the increase in specific Raman intensity ratio; and (4) reducing bilayer tension with increasing serotonin concentrations. Overall, membrane modifications increase with rising serotonin concentrations, plateauing at higher levels. Sensitivity to serotonin varies by lipid composition in the order: DOPC/DOPS ≈ DOPC/Sphingomyelin/Cholesterol > DOPC. Our experimental findings reveal that serotonin significantly alters membrane properties, particularly affecting neuronal membrane composition and lipid rafts, which are critical for membrane protein organization and signaling. These findings suggest that serotonergic drugs and pathological fluctuations in serotonin may influence signaling not only through classical receptor-mediated pathways, but also by altering the lipid–protein landscape of the membrane, with potential implications for drug efficacy, off-target effects, and the development of therapies that target membrane composition in serotonin-related disorders.

The emergence of resistance to SARS-CoV-2 main protease (M^pro) inhibitors such as nirmatrelvir poses a significant threat to the long-term effectiveness of COVID-19 antivirals. Ibuzatrelvir (PF-07817883) and ensitrelvir are next-generation M^pro inhibitors with enhanced metabolic stability, eliminating the need for coadministration with ritonavir, unlike nirmatrelvir. Ibuzatrelvir is currently in Phase 3 clinical trials in the United States, and ensitrelvir is approved in Japan. In this study, we assessed the cross-resistance of ibuzatrelvir, nirmatrelvir, and ensitrelvir against a panel of clinically relevant M^pro mutants using FRET-based enzymatic assays, thermal shift binding assays, and cell-based antiviral plaque assays. Our results reveal a cross-resistance pattern of ibuzatrelvir, nirmatrelvir, and ensitrelvir against Q192, S144, H172, and E166 mutants. Notably, the recombinant SARS-CoV-2 virus containing the M^pro L50F/E166A/L167F triple mutant is highly resistant to all three drugs in the antiviral plaque assay. These findings underscore the challenge posed by E166 mutations and highlight the need for resistance-resistant M^pro inhibitors as future therapeutics.

The gut microbiota are a dynamic ecosystem that is crucial for immune regulation and maintenance of intestinal barrier integrity. Dysbiosis within this community contributes to the chronic inflammation characteristic of inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, for which no definitive cure currently exists. This comprehensive review examines recent preclinical and clinical studies on how anthocyanin-polyphenolic pigments, such as cyanidins and malvidins, modulate gut microbial communities, reduce intestinal inflammation, and counteract age-related declines in immune homeostasis. We analyzed the literature on anthocyanin–microbiota interactions in IBD pathogenesis, focusing on cytokine profiles, barrier function assays, lipopolysaccharide synthesis, oxidative stress markers, and short-chain fatty acid production. Additionally, we explored the relationship among cellular senescence, the senescence-associated secretory phenotype (SASP), and microbiome shifts during intestinal aging. Evidence indicates that anthocyanins consistently suppress key pro-inflammatory cytokines, such as interleukin-1β, interleukin-6, TNF-α, and interferon-γ, while preserving mucosal architecture and reducing lipopolysaccharide load and mitochondrial oxidative phosphorylation. These compounds help to restore microbial balance, promote short-chain fatty acid synthesis, and enrich bacterial taxa associated with barrier integrity. In aging models, anthocyanins attenuate oxidative stress, stabilize redox homeostasis, inhibit senescence signaling and SASP secretion, and partially restore anti-inflammatory interleukin-10 levels. In conclusion, anthocyanins are promising dietary therapeutics for IBD management and for mitigating intestinal aging. Future research should transition from murine models to human clinical trials by integrating senolytic strategies, targeted microbiome modulation, and pharmacological dissection of the senescence–microbiome axis to foster disease prevention and promote healthy aging.

Altogether, 60–70% of the ATP-binding cassette (ABC) and solute carrier (SLC) transporters can currently not be targeted by drugs, despite their involvement in human diseases. The design of potential drug candidates relies on hit identification and subsequent optimization with regard to selectivity and specificity. However, these workflows ultimately fail if no hit molecules can be found. We pursued a strategy of rational discovery of hit molecules for ‘undruggable’ ABC and SLC transporters based on polypharmacology as an alternative approach in the drug development repertoire. The 42 most polypharmacological ABC transporter modulators were profiled against eight specific (NAT, DAT, and SERT) and polyspecific (OCT1–3, MATE1–2K) SLCs. The general hit rate increased expectedly with the degree of polyspecificity, ranging from 0 to 9.52% (NAT, DAT, SERT) to 19.0–52.4% (OCT1–3, MATE1–2K). Striking was the hit rate for potent drugs, which was highest for the specific transporter SERT (75.0%); additionally, pranlukast (PRA) could also be identified as common substrate of NAT, DAT, SERT, and MATE2K. The polypharmacology of drugs correlated with their potency, and a higher degree of polypharmacology against ABCs was reflected in a higher degree of polypharmacology against SLCs. Some compounds mediated between both specific and polyspecific transporters which could be underpinned by the identification of common molecular features (‘privileged structures’). The polypharmacology of selected drugs could be transferred to ABCA1 and Oatp1d1, two transporters for which almost no modulators have been reported before. This strategy provided privileged ligands with high potency at high hit rates to challenge transporter undruggability.

Liver fibrosis and hepatocellular carcinoma (HCC) remain major global health burdens, in part due to limited drug specificity, off-target toxicity, and the complex hepatic microenvironment. Peptide-functionalized liposomal nanocarriers have emerged as a promising approach to enhance cell-selective drug delivery to activated hepatic stellate cells in fibrosis and malignant hepatocytes in HCC. This review critically examines recent progress in peptide-guided liposomal systems, focusing on design strategies, receptor-mediated targeting mechanisms, and translational considerations. Key peptide ligands, including cyclic RGD peptides targeting integrins αvβ3/αvβ5, GE11 for epidermal growth factor receptor, and transferrin receptor-binding peptides, are discussed in relation to their roles in promoting receptor-mediated endocytosis. Liposome fabrication methods and ligand conjugation chemistries are evaluated for their impact on stability, ligand presentation, and in vivo biodistribution. Preclinical evidence demonstrating improved drug accumulation, reduced fibrosis markers, and suppression of tumor growth is summarized alongside current limitations including receptor heterogeneity, extracellular matrix barriers, and manufacturing scalability. Finally, emerging directions such as stimuli-responsive and theranostic liposomes as well as combination strategies with immunomodulatory therapies are highlighted. By integrating mechanistic insight with design and translational perspectives, this review identifies key opportunities and the remaining hurdles in advancing peptide-targeted liposomal nanomedicines for liver disease.

Proteolysis-targeting chimeras (PROTACs) and degraders have been developed against the hRpn13 fragment hRpn13^Pru that is present in various cancer types. Testing the performance of these hRpn13^Pru-targeting compounds in pharmacokinetic and efficacy studies has been stymied, however, by their poor solubility. Here, we develop a rapid and cost-effective platform to Screen and Characterize small molecule Nanosuspensions (SCaN). We discovered that the hRpn13^Pru degrader XL44 adopts a crystalline state, preventing its bioavailability. The first phase of SCaN screens vehicles to identify lead XL44 nanosuspension formulations based on particle size consistency, including in biorelevant media, while the second phase evaluates stability over time. The lead nanosuspensions are then advanced to the third phase of SCaN to assess their physical and colloidal stability. This pipeline allows the formulation of poorly soluble compounds for single-dose pharmacokinetic and pilot multidose tumor mouse studies. We additionally analyzed our XL44 formulation morphologically by atomic force microscopy to find that the XL44 nanoparticles are predominantly globular, with a small population of rod-like particles. Using the optimal nanosuspension determined by SCaN, XL44 slowed tumor growth in a myeloma xenograft model at 35% inhibition with a 48–72 mg/kg treatment regimen. This case study is the first in vivo demonstration that hRpn13^Pru-targeting degraders can inhibit tumor growth, and the efficacy shown here motivates the development of more potent hRpn13^Pru degraders. Broadly, our SCaN platform is designed for poorly soluble drug candidates to allow for pilot in vivo testing.

Cystinosis is an inherited lysosomal storage disorder characterized by the intralysosomal accumulation of crystals of cystine. This alteration is caused by the absence of the lysosomal membrane transporter cystinosin, which leads to clinical manifestations of the disease. Oral administration of aminothiol cysteamine, while not a curative therapy, has proven to be effective in controlling the progress of the disease and reducing its complications. However, the numerous side effects inherent to the treatment are responsible for low patient compliance, severely impacting therapy success. Several studies have been performed in the past few years with the aim of optimizing cysteamine therapy to avoid its main drawbacks. This review focuses on the potential and feasibility of these novel strategies. As well, it introduces novel recent approaches studied as an alternative or complement to cysteamine treatment.

Failure to resolve the neutrophilic inflammation during the innate immune response results in neutrophil accumulation in the airways. These cells exhibit prolonged survival, increased necrosis, and impaired phagocytic capacity. Paradoxically, despite reduced pathogen-clearing ability, neutrophils release serine proteases that drive the destruction of airway tissue. Their persistence in the lung chronically promotes a cycle of tissue damage, remodeling, and inflammation, leading to progressive pulmonary dysfunction. Recent discoveries in neutrophil dysregulation open up the possibility of developing more targeted, disease-specific therapies, potentially revolutionizing the treatment of diseases like cystic fibrosis, chronic obstructive pulmonary disease, bronchiectasis, and asthma, where current treatments remain largely generalized and ineffective. This review explores the complex relationship between neutrophil dysregulation and disease progression, highlighting the different roles that neutrophils play across various lung diseases, and will summarize current strategies to target key pathways. Understanding these pathways could inform the development of therapeutic strategies to effectively mitigate neutrophil-driven inflammation to improve the clinical outcome.