ACS Pharmacology and Translational Science最新文献

Dysregulated immune responses to domestic allergens are underlying events in atopic dermatitis (AD), an inflammatory disease of humans and domestic companion animals characterized by itching and eczema. The house dust mite (HDM) allergome, notably the cysteine protease group 1 allergens, is an important trigger of AD. This protease activity is implicated in innate mechanisms which both initiate and reinforce allergic sensitization, prompting interest in the design of protease inhibitors as a novel allergy therapy. We examined pyruvamide chemotype protease inhibitors on intracellular reactive oxidant species (ROS) production induced by HDM allergen extracts in HaCaT keratinocytes and identified promising topical and orally bioavailable candidates. We then explored the wider signaling network affected by this allergen inhibition in keratinocytes and airway epithelial cells (AECs). Optimized pyruvamides with different properties (viz. neutral vs charged, cell-impermeant molecules) inhibited ROS generation evoked by HDM allergen extract, but biochemical potency against Der p 1 per se was not a direct indicator of cellular efficacy. ROS production was stimulated by Der p 1 through canonical activation of protease-activated receptor 1 which propagated the activation signal through a network involving ATP, purinoceptors, transient receptor potential channels, nitric oxide formation, and the ligation of Toll-like receptor (TLR) 4 and TLR 1/2 heterodimers by endogenous activators. These data reveal that inhibition of a single allergen in HDM allergenic extracts prevents an extensive signaling network which is coupled to the redox control of keratinocytes and AECs. These data underscore the exciting possibility that allergic responses can be inhibited at source.

Prostate cancer (PCa) is the most common cancer and the second leading cause of death among men worldwide. Significant progress has been made in managing PCa by targeting the prostate-specific membrane antigen (PSMA), which holds great promise for improving the accuracy and effectiveness of diagnosis. Previously, we reported a high-affinity glutamate–urea–lysine (EuK)-based PSMA-targeting tracer, BQ0413, containing the maE₃ chelator for labeling with technetium-99m for single-photon emission tomography diagnostic imaging. BQ0413 demonstrated efficient tumor targeting in PCa patients with concomitant elevated activity retention in the kidneys, which is typical for EuK-based PSMA-targeting tracers. We hypothesized that a decrease in the tracer’s total negative charge, by substituting negatively charged glutamate residues in the maE₃ chelator with polar neutral serine, could decrease activity retention in the kidneys. The present study aimed to evaluate the tumor targeting and biodistribution profile of two new PSMA-targeting tracers, BQ0500 (maESE) and BQ0501 (maS₃), in comparison to BQ0413 (maE₃). Conjugates were successfully radiolabeled with technetium-99m and characterized in vitro and in vivo. [^99mTc]Tc-BQ0500 and [^99mTc]Tc-BQ0501 demonstrated PSMA-specific binding to PC3-pip cells with picomolar affinity; however, the affinity was 3–5-fold compromised in comparison with the reference [^99mTc]Tc-BQ0413. Full replacement of glutamate residues by serines in [^99mTc]Tc-BQ0501 resulted in an improved overall clearance from normal organs with a moderately increased accumulation of activity in the gastrointestinal tract. [^99mTc]Tc-BQ0501 demonstrated efficient tumor targeting and improved tumor-to-background ratios. These results suggest that chelator modifications, such as charge alteration, play a critical role in improving tumor targeting and pharmacokinetics for EuK-based PSMA-targeting tracers.

Selective chemical probes are essential for dissecting biological pathways and advancing drug discovery, yet developing high-quality probes for targets such as the aldehyde dehydrogenase (ALDH) family remains challenging. Here, we present a novel integrated approach combining experimental quantitative high-throughput screening (qHTS) with advanced machine learning (ML) and pharmacophore (PH4) modeling to rapidly identify selective inhibitors across multiple ALDH isoforms. We screened ∼13,000 annotated compounds against biochemical and cellular assays. We then utilized the data set to build ML and PH4 models to virtually screen a larger set of 174,000 compounds to enhance the chemical diversity of hits. This approach led to the expansion of chemically diverse isoform-selective inhibitors that are potent in both biochemical and cell-based assays. Validation through cellular target engagement assays further confirmed the selective activity of these compounds, leading to the discovery of ALDH1A2, ALDH1A3, ALDH2, and ALDH3A1 chemical probe candidates. Remarkably, this was achieved by employing just a single iteration of quantitative structure–activity relationship (QSAR) and PH4 modeling for virtual screening. This combined in vitro and in silico strategy not only enhances the discovery of biologically relevant chemical probe candidates but also significantly expands the chemical diversity accessible for probe development, establishing a new platform for the rapid and resource-efficient identification of chemical probes against the ALDH enzyme family. The data set generated, including hundreds of compounds thoroughly characterized across a spectrum of assays, is publicly available and can serve as a high-quality training set for future research initiatives and probe development efforts.

Antenatal depression, or depression during pregnancy, is a common psychiatric disorder and poses significant risks to both the mother and the fetus. Despite these risks, it is frequently left untreated due to fears of side effects caused by antidepressant medications which cross through the placental barrier. It is therefore desirable to develop formulation strategies to mitigate systemic exposure to psychotropics while maintaining their efficacy. In this work, we develop formulations of sertraline, a common antidepressant, to target delivery to the brain through intranasal administration. Formulation engineering enables successful solubilization of sertraline at high concentrations over months at room temperature. Using mice, we compare sertraline biodistribution following intranasal administration and standard oral administration. Intranasal administration of our candidate formulation provides comparable brain exposure at half the dose compared to oral treatment and lowers the maximum plasma exposure. These findings suggest that intranasal administration may provide selectivity for drug exposure in the central nervous system over systemic exposure.

In many autoimmune pathologies, including Rheumatoid Arthritis (RA), only a small percentage of the total B cell population is autoreactive and sustain disease. Yet, current immunotherapy treatments often eliminate the entire B-cell population, leading to immune deficiency. We developed an approach to selectively eliminate autoreactive B cells with targeted photodynamic therapy (tPDT). We designed a construct containing a dimeric peptidic antigen (diCCP4) that selectively binds a patient-derived autoreactive B cell receptor (BCR) and additionally included the photosensitizer IRDye700DX. We tested the construct on a modified Ramos B-cell line (Ramos 3F3), expressing this specific autoreactive BCR sequence. After brief exposure to 689 nm light, the photosensitizer selectively eliminates the modified Ramos cells, while the construct is not cytotoxic to cells lacking the autoreactive BCR. In a 3D coculture of the Ramos autoreactive B cell line with peripheral blood mononuclear cells (PBMCs) we observed only a minimal response of the untargeted cells. These results highlight the potential of tPDT against autoreactive B cells in autoimmune disease.

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic pathology currently treated with two antifibrotic drugs, nintedanib and pirfenidone; however, more effective and safer cell-specific therapeutic agents are needed to overcome their limited efficacy and tolerability. αvβ6 integrin is a clinically validated fibrosis biomarker, and several αvβ6-targeted small molecules and positron emission tomography (PET) tracers have recently proven their therapeutic and diagnostic potential in IPF. Surprisingly, αvβ6-targeted and fibrosis-related drug conjugates are still lacking. Two molecular conjugates, namely the previously reported peptide–drug conjugate (PDC) 1 and the novel fluorescent probe 2, were developed here, where a αvβ6-targeted cyclopeptide is covalently linked to either nintedanib or the near-infrared (NIR) ZW800-1 fluorescent tag via robust linkers. Chemical synthesis of the two compounds, molecular docking studies of 1 in complex with αvβ6, mouse and human plasma stability measurement, binding affinity evaluation toward the isolated αvβ6 receptor, and in vitro human IPF-derived fibroblast cell internalization and antifibrotic studies were performed. Then, in vivo and ex vivo assessments of the antifibrotic efficacy of 1 and the diagnostic potential of 2 were carried out in a bleomycin (BLM)-induced lung fibrosis mouse model. Conjugate 1 demonstrated superior antifibrotic efficacy as compared to the separated peptide and drug components, and probe 2 specifically accumulated in the fibrotic lesions of mice lungs. The molecular conjugates 1 and 2 represent a promising theranostic couple for lung fibrosis and αvβ6-related pathologies and a useful proof-of-principle tool testifying how the simultaneous cell-targeted inhibition of multiple fibrosis-related receptors could be more impactful than the inhibition of one sole receptor.

Prior research has determined that music plays a central role in psychedelic assisted therapy (PAT). While there is a general consensus of the importance of music during PAT, there are only three empirical studies published to date that directly investigate which type of music might best support PAT. Importantly, no review to date has critically analyzed these studies and identified the gaps. Careful examination reveals these studies have important limitations and the findings lack alignment with other publications and existing recommendations. Additionally, our understanding of guidelines seems to be not much different from when this research started in 1970. This paper summarizes the common impacts of music during PAT, reviews what we know about music selection and guidelines for PAT, and makes suggestions of priorities for future research.

p-Cresol (pC) is a phenolic compound to which humans can be exposed through both environmental sources, such as a pollutant, and endogenous production by the gut microbiota. Among microbial contributors, Clostridioides difficile appears to be a major source of pC within the body. Once absorbed, pC is highly protein-bound in plasma and predominantly circulates in its hepatic conjugated forms: p-cresyl sulfate (pCS) and p-cresol glucuronide (pCG), which are mainly excreted in urine. Accumulation of these metabolites, particularly pCS, classified as a protein-bound uremic toxin, has been associated with the progression of chronic kidney disease (CKD) and related complications, due to its pro-oxidant, pro-inflammatory, and pro-apoptotic properties. CKD patients are at increased risk for cognitive impairment, affective disorders, and central nervous system (CNS) dysfunctions. In recent years, increasing evidence has suggested a potential role of pC and its metabolites in CNS diseases. Here, we summarize current knowledge on the involvement of these compounds in the pathogenesis and progression of autism spectrum disorder, Parkinson’s disease, Alzheimer’s disease, and post-traumatic stress disorder. We also discuss how modulating systemic levels of pC may represent a promising strategy to improve pathological phenotypes in the context of neurodevelopmental and neurodegenerative disorders.

Glioblastoma multiforme (GBM) is the most aggressive and prevailing form of primary brain tumor, illustrated by its rapid growth and invasive nature. GBM continues to be highly incurable despite advancements in treatment due to its complex tumor microenvironment (TME) and the unique characteristics of tumor-associated macrophages (TAMs). This review explores the function of macrophages within the TME of GBM, specifically emphasizing the impact of colony-stimulating Factor-1 (CSF-1) and its receptor CSF1R in macrophage biology. The progression, survival, and differentiation of TAMs, which often rely on immunosuppressive properties that contribute to tumor growth and treatment resistance, are facilitated by elevated CSF-1 levels in GBM. The inhibition of CSF1R presents a promising therapeutic strategy, as it selectively targets tumor-promoting macrophages while sparing antitumor macrophages. Preclinical evidence demonstrates improved survival outcomes through CSF1R inhibition in mouse models, highlighting its potential for clinical application. Ongoing clinical trials further investigate this approach, aiming to enhance treatment efficacy for patients with GBM. This review concludes by emphasizing the significance of repolarizing macrophages as a novel therapeutic opportunity in GBM management, alongside emerging trends and future research directions that could lead to breakthroughs in treatment strategies.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID (LC) are increasingly recognized as debilitating postinfectious conditions that impact both individuals and society. Recent research highlights the potential of metformin, an antidiabetic agent, as a treatment for these syndromes by targeting their underlying mechanisms. This review assesses the effectiveness of metformin in ME/CFS and LC, which involve complex dysfunctions related to cytokines, glycolysis, ATP generation, oxidative stress, gastrointestinal microbiomes, and vascular endothelial function. Metformin, traditionally known for its antihyperglycemic properties may offer broader therapeutic benefits by influencing these pathological pathways. It works by inhibiting complexes I and IV of the electron transport chain, which reduces the strain on malfunctioning complex V and decreases the production of harmful free radicals. Additionally, metformin’s impact on mTOR signaling could improve energy metabolism in ME/CFS and LC by downregulating an overactive but underperforming protein, thereby alleviating symptoms. Beyond the impact on cellular metabolism, metformin has shown to have anti-inflammatory, vascular, gastrointestinal, neuroprotective and epigenetic effects. We explore this impact of metformin and the potential role it could play to help people with ME/CFS. While metformin shows promise, it is unlikely to be a stand-alone solution. Instead, it may be part of a broader treatment strategy that includes other therapies targeting neurocognitive and autonomic impairments.