Pharmacology Cambridge RSS Paper feed

Nat Cardiovasc Res. 2026 Feb 6. doi: 10.1038/s44161-026-00776-9. Online ahead of print.

ABSTRACT

Myocardial injuries lead to cardiomyocyte loss and heart failure. Endogenous glucocorticoids, via the glucocorticoid receptor (GR), limit cardiomyocyte regeneration. Here we show that glucocorticoids suppress mammalian (murine) cardiomyocyte proliferative response to regenerative growth factors and cytokines. GR activation in neonatal cardiomyocytes upregulated MAPK-ERK inhibitors ERRFI1 and DUSP1. Using neuregulin 1 as a model, we demonstrated that glucocorticoids inhibit growth-factor-induced ERK activation, nuclear translocation and transcriptional output. Errfi1 and Dusp1 knockdown restored growth-factor-induced proliferation of glucocorticoid-exposed cardiomyocytes. Cardiac expression of DUSP1 and ERRFI1 increased postnatally, coinciding with regenerative capacity decline. In juvenile and adult cardiomyocytes, regenerative growth factors failed to induce the MAPK-ERK pathway and proliferation; however, DUSP1 inhibition restored these responses. GR antagonism enhanced growth-factor-induced cardiomyocyte protection, proliferation and cardiac function after adult myocardial injury. These findings reveal the emergence of a postnatal systemic brake on cardiomyocyte proliferative response to growth factors and support GR inhibition as a strategy to enhance growth-factor-based regenerative therapies.

PMID:41652035 | DOI:10.1038/s44161-026-00776-9

Science. 2026 Feb 5;391(6785):553-554. doi: 10.1126/science.aee5778. Epub 2026 Feb 5.

ABSTRACT

DNA origami scaffolds displaying HIV antigens stimulate focused antibody responses in mice.

PMID:41643031 | DOI:10.1126/science.aee5778

Bioconjug Chem. 2026 Jan 24. doi: 10.1021/acs.bioconjchem.5c00519. Online ahead of print.

ABSTRACT

Cell-surface conjugation has enormous therapeutic and research potential. Existing technologies for cell-surface modification are usually reversible, nonspecific, or rely on genetic editing of target cells. Here, we present the NanoBondy, a nanobody modified for covalent ligation to an unmodified protein target at the cell surface. The NanoBondy utilizes the 20 naturally occurring amino acids, harnessing NeissLock chemistry engineered from Neisseria meningitidis. We evaluated the binding and specificity of a panel of nanobodies to CD45, a long-lived surface marker of nucleated hematopoietic cells. We demonstrated the conversion of existing nanobodies to covalently reacting NanoBondies using a disulfide clamp to position the self-processing module of FrpA close to the nanobody antigen-binding site. The addition of calcium induces anhydride formation at the NanoBondy C-terminus, enabling proximity-directed ligation to surface amines on CD45. We optimized the NanoBondy reaction by fine-tuning linkers and disulfide clamp sites to modulate anhydride positioning. Tandem mass spectrometry mapped reaction sites between NanoBondy and CD45. NanoBondy ligation was robust to buffer, pH, and temperature and was detected within 2 minutes. We established the reaction specificity of NanoBondies to endogenous CD45 at the surface of NK cells and T cells. NanoBondy technology provides a modular approach for targeted, inducible, and covalent cell-surface modification of immune cells without their genetic modification.

PMID:41578972 | DOI:10.1021/acs.bioconjchem.5c00519

JACS Au. 2025 Nov 14;5(12):5917-5923. doi: 10.1021/jacsau.5c01209. eCollection 2025 Dec 22.

ABSTRACT

DNA nanotechnology has emerged as a promising field for biomedical applications, in both the therapeutic and diagnostic domains. The ability of DNA nanostructures to carry cargos in precise numbers and orientations makes them competitive candidates for drug delivery, biosensors, or imaging agents. Two of the main challenges for translating DNA nanostructures from the laboratory to the clinic are achieving cost-effective large-scale production and establishing comprehensive safety profiles. Having the ability to reliably and efficiently purify functionalized DNA nanostructures is key to both challenges and an open question in the field of DNA nanotechnology. Here we present a scalable method for the fast and efficient purification of a high concentration of peptide- or protein-functionalized DNA nanostructures. We use a gravity-driven size exclusion chromatography approach that has the potential to purify DNA nanostructures within 10 min in yields of up to 93% with purities of over 99.9% and is appropriate for both protein and peptide conjugates.

PMID:41450627 | PMC:PMC12728597 | DOI:10.1021/jacsau.5c01209

Brain Neurosci Adv. 2025 Dec 15;9:23982128251406340. doi: 10.1177/23982128251406340. eCollection 2025 Jan-Dec.

ABSTRACT

On 10-11 September 2025, the Cambridge Neuroscience Interdisciplinary Research Centre held its eighth biennial symposium on the topic of Interventions and Recovery. The meeting saw basic and clinical neuroscientists come together from Cambridge and beyond to discuss the latest advancements in cell and gene therapies, pharmaceutical innovations and cutting-edge neurotechnology aimed at addressing neurological diseases. Here, we provide a summary of the meeting, which shined a light on reasons to be optimistic for the future of treating conditions of the nervous system.

PMID:41415128 | PMC:PMC12708998 | DOI:10.1177/23982128251406340

bioRxiv [Preprint]. 2025 Nov 29:2025.11.26.690749. doi: 10.1101/2025.11.26.690749.

ABSTRACT

Small molecule activators of protein phosphatase 2A (PP2A), hereafter SMAPs, have attracted substantial interest, for their potential to inhibit cancer cell proliferation by targeting PR65, the scaffold subunit of the PP2A heterotrimer. PR65 is a uniquely flexible and stable molecule composed of 15 tandem HEAT (Huntingtin, Elongation factor 3-PP2A-TOR1) repeats. We characterized the binding sites and interactions of two SMAPs ATUX-8385 and DT-061 with PR65 and evaluated effects on PR65 structural dynamics using docking and molecular dynamics simulations. We initiated SMAP-bound PR65 simulations starting from two binding sites: S1, determined by cryo-electron microscopy for DT-061 bound to PP2A, on the inner helices of the HEAT repeats 2 and 3 (2i and 3i); and S2, predicted by docking of ATUX-8385 onto PR65, on 4i and 5i and outer helices 5o and 6o consistent with footprinting experiments. S2 proved to be a stable site for both SMAPs when initiating the simulations at S2. However, neither DT-061 nor ATUX-8385 demonstrated stable binding to S1. DT-061 rapidly dissociated from S1 to settle instead at a neighboring site S4 overlapping with our previously identified S3 for PR65 in extended form, suggesting that binding to S1 may be a 2-step process: an initial binding to PR65 alone, either to S3/S4 or S2, followed by movement to S3/S4, and then an induced relocation to S1 upon complexation with the regulatory and catalytic subunits. Targeted in silico mutagenesis showed that mutations at S2 and S4 destabilized SMAP binding to the PR65 (subunit). Heterotrimeric PP2A simulations showed that S3 and S4 binding were not persistent upon complexation. Together, these results corroborate our findings. Furthermore, preferentially stabilized a relatively extended PR65 conformation that would accommodate, if not promote, the assembly of the catalytic and regulatory subunits to prompt the activation of the trimeric phosphatase.

PMID:41394555 | PMC:PMC12697531 | DOI:10.1101/2025.11.26.690749

Biophys Rev. 2025 Jul 28;17(4):1119-1132. doi: 10.1007/s12551-025-01343-5. eCollection 2025 Aug.

ABSTRACT

The material properties of biomolecular condensates, such as interfacial tension, viscoelasticity, stiffness, and molecular dynamics, are crucial for their biological functions in processes like signal transduction, stress response, and gene regulation. These properties influence both endogenous condensates, like the nucleolus and stress granules, and synthetic condensates engineered for potential drug delivery applications. In vitro studies, using purified components, provide controlled environments to explore the fundamental physics of phase separation, offering high precision in manipulating molecular components and conditions. However, cell-based characterisations are indispensable for understanding the physiological relevance of biomolecular condensates, accounting for molecular crowding, post-translational modifications, and interactions with cellular structures. Light-microscopy techniques offer the potential to bridge in vitro findings with in cellulo behaviour. This review outlines some fundamental challenges of in cellulo studies and discusses the potential of fluorescently labelling biomolecular condensates using the tetracysteine tag/biarsenical dye strategy. We describe how fluorescence-based techniques, including fluorescence recovery after photobleaching (FRAP) and emerging techniques like fluorescence lifetime imaging microscopy (FLIM), flicker spectroscopy, and raster image correlation spectroscopy (RICS), may be used to gain a detailed understanding of the material properties of biomolecular condensates within the cellular environment. Finally, we discuss the potential of Brillouin light scattering (BLS) microscopy, a label-free technique that holds potential for deciphering the cellular biophysics of biomolecular condensates.

PMID:41378109 | PMC:PMC12686230 | DOI:10.1007/s12551-025-01343-5

Methods Enzymol. 2025;724:83-97. doi: 10.1016/bs.mie.2025.09.018. Epub 2025 Oct 14.

ABSTRACT

Multidrug transporters are membrane proteins that confer antibiotic resistance on bacterial cells by actively extruding toxic compounds. NorM from Vibrio cholerae (NorM-VC) belongs to the MATE (Multidrug And Toxic compound Extrusion) family and is active as an ion/antibiotic exchanger. With the availability of high-resolution crystal and cryo-EM structures, and mechanistic predictions for NorM proteins, there is a need for convenient activity measurements in non-pathogenic cells and cell mimics. Here, we outline methods for the expression and purification of NorM-VC, protein reconstitution in proteoliposomes, and transport activity measurements in Lactococcus lactis and proteoliposomes using doxorubicin as the substrate. These measurements can easily be adapted for high throughput measurements in multi-well plates and extended to other classes of multidrug transporters that use doxorubicin as a substrate.

PMID:41309185 | DOI:10.1016/bs.mie.2025.09.018

bioRxiv [Preprint]. 2025 Oct 22:2025.10.21.683747. doi: 10.1101/2025.10.21.683747.

ABSTRACT

Global health remains threatened by spillovers of zoonotic SARS-like betacoronaviruses (sarbecoviruses) that could be mitigated by a pan-sarbecovirus vaccine1. We described elicitation of potently neutralizing and cross-reactive anti-sarbecovirus antibodies by mosaic-8 nanoparticles (NPs) displaying eight different sarbecovirus spike receptor-binding domains (RBDs) as 60 copies of eight individual RBDs2-6 (mosaic-8 RBD-NPs) or 30 copies of two "quartets," each presenting four tandemly-arranged RBDs7 (dual quartet RBD-NPs). To facilitate manufacture of a broadly protective mosaic-8 vaccine, we generated membrane-bound RBD quartets that can be genetically encoded and delivered via mRNA: dual quartet RBD-mRNA and dual quartet RBD-EABR-mRNA, which utilizes ESCRT- and ALIX-binding region (EABR) technology that promotes immunogen presentation on cell surfaces and circulating enveloped virus-like particles (eVLPs)8. Immunization with mRNA immunogens elicited equivalent or improved binding breadths, neutralization potencies, T cell responses, and targeting of conserved RBD epitopes across sarbecoviruses, demonstrating successful conversion of protein-based mosaic-8 RBD vaccines to mRNA formats. Systems serology9 showed that the mRNA vaccines elicited balanced IgG subclass responses with increased Fcγ receptor-binding IgGs, consistent with potentially superior Fc effector functions. A new technique, Systems Serology-Polyclonal Epitope Mapping (SySPEM), revealed distinct IgG-subclass-specific epitope targeting signatures across mRNA and protein-based vaccine modalities. These results demonstrate successful conversion of mosaic-8 RBD-NPs to mRNA or EABR-mRNA vaccines that provide easy manufacturing and enhanced protection from future pandemic sarbecovirus outbreaks.

PMID:41280075 | PMC:PMC12633426 | DOI:10.1101/2025.10.21.683747

Mol Med. 2025 Nov 23. doi: 10.1186/s10020-025-01398-w. Online ahead of print.

NO ABSTRACT

PMID:41276822 | DOI:10.1186/s10020-025-01398-w

Nat Commun. 2025 Nov 20;16(1):10240. doi: 10.1038/s41467-025-65473-w.

ABSTRACT

A major regulator of gastrointestinal physiology is the enteric nervous system. This division of the autonomic nervous system is unique in its extensiveness, with neurons distributed from the esophagus to the rectum, and its capability for local information processing. However, the constant motion of the gut, arising from its relative movements in the peritoneal cavity and the peristaltic movements associated with gut motility, as well as the sparse distribution of the neurons constituting the enteric nervous system, has made access and analysis exceedingly challenging. Here, we present the construction and validation of a bioelectronic implant for accessing neural information from the distal colon. Our bioelectronic monitoring system demonstrates real-time electrophysiological recording in response to chemical and mechanical distension under anesthesia and to feeding and stress in freely-moving animals. Direct access to the communication pathways of the enteric nervous system paves the way for neuromodulation strategies targeting the gut-brain axis.

PMID:41266383 | DOI:10.1038/s41467-025-65473-w

J Mol Biol. 2025 Nov 17:169549. doi: 10.1016/j.jmb.2025.169549. Online ahead of print.

ABSTRACT

Multidrug and toxic compound extrusion (MATE) transport proteins contribute to multidrug resistance in human pathogens by extruding various cytotoxic compounds from the cellular interior. Despite their importance across all domains of life, the specificities and mechanisms of substrate transport of these proteins remain poorly understood due to limited structural and functional information. Here, we determined the cryo-electron microscopy structure of NorM from Vibrio cholerae (NorM-VC) in complex with the anthracycline antibiotic doxorubicin, using the NabFab approach. The structure reveals that the doxorubicin-binding pocket is located halfway through the membrane, within the C-lobe of the protein. Functional studies targeting the doxorubicin-interacting residues validated the binding pocket and enabled detailed analysis of the doxorubicin transport reaction. Our findings indicate doxorubicin binding within a multisite binding chamber engaged in a general transport mechanism for a variety of substrates.

PMID:41260293 | DOI:10.1016/j.jmb.2025.169549

J Neurosci. 2025 Nov 12;45(46):e1309252025. doi: 10.1523/JNEUROSCI.1309-25.2025.

ABSTRACT

Pain is a symptom common to a wide variety of conditions and one that severely impacts an individual's everyday life, as well as having broader socioeconomic repercussions. In recent years, there has been spectacularly rapid progress in the understanding of the molecular basis of sensory neuron function and pain in preclinical models. However, the number of analgesics interacting with novel targets that have received regulatory approval in recent years has been limited. Examples include monoclonal antibody and small molecule therapies disrupting calcitonin gene-related peptide signaling for treating migraine and, most recently, suzetrigine, a small molecular inhibitor of the voltage-gated sodium channel NaV1.8 subunit. In this review, we step away from focusing on the sensory neuron as the transmitter of nociceptive information and examine the role of non-neuronal cells in modulating sensory neuron activity. One potential appeal of disrupting the activity of peripherally located non-neuronal cells is the likely bypassing of side effects associated with modulating a target receptor that is expressed by neurons within both the peripheral and central nervous systems, although targeting of peripheral, non-neuronal cells will not of course necessarily be side effect-free. Here, we examine the key roles of non-neuronal cells in orchestrating pain across a diverse set of conditions, from joint pain to bone pain, chemotherapy-induced neuropathic pain, Fabry disease, and chronic pain in general.

PMID:41224654 | DOI:10.1523/JNEUROSCI.1309-25.2025

Cancer Heterog Plast. 2025;2(4):10.47248/chp2502040018. doi: 10.47248/chp2502040018. Epub 2025 Oct 17.

ABSTRACT

The inaugural FASEB Science Research Conference (SRC) on Cellular Plasticity in Cancer was held in May 2025 in Hong Kong SAR, China. This event brought together leading experts to discuss cutting-edge research centered on cancer cell plasticity. The conference featured comprehensive presentations covering a broad spectrum of topics, including oncofetal reprogramming in tumor development and progression, mechanisms regulating cancer cell plasticity, metabolic reprogramming and its role in tumor progression, cancer cell plasticity during metastasis, cancer stem cell programs within the tumor microenvironment, tumor plasticity and immune evasion, as well as innovative therapeutic strategies aimed at targeting stem cell-like states, modulating cancer cell states, and effectively controlling disease progression. It is anticipated that the insights gained from this meeting will catalyze further advancements in cancer biology and therapy.

PMID:41221269 | PMC:PMC12599846 | DOI:10.47248/chp2502040018

J Chem Inf Model. 2025 Nov 11. doi: 10.1021/acs.jcim.5c01120. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic human pathogen. One of the most potent virulence factors in its arsenal is the type III secretion system (T3SS). This secretion apparatus injects effector toxins directly into host cells, thereby causing cytotoxicity. The expression of all components of T3SS is regulated by a master transcriptional regulator, ExsA. The inhibition of the latter should therefore lead to the suppression of P. aeruginosa virulence. However, to date, no drugs targeting ExsA have reached the market, and only static structural models of the protein have been generated, focusing on the C-terminal domain (CTD). Here, we used μs atomistic molecular dynamics (MD) simulations to investigate the conformational dynamics of full-length ExsA bound to DNA or DNA free, investigated as monomers or dimers. Our data show how the CTD and NTD of ExsA likely interact with one another and how ExsA binds to DNA. We also analyzed the MD trajectories to predict potential druggable pocket(s) in the structure and relevant geometry. This revealed a lipid-binding pocket within the β-sheet bundle and identified two novel potentially druggable pockets at the NTD/CTD interface, which could be used in future structure-based drug discovery campaigns. Overall, a single helix-turn-helix motif seems to drive DNA recognition in each ExsA monomer and to stabilize the putative ligand-binding domain.

PMID:41219151 | DOI:10.1021/acs.jcim.5c01120

Cell Mol Gastroenterol Hepatol. 2025 Nov 4:101671. doi: 10.1016/j.jcmgh.2025.101671. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Localised acidification from immune cell infiltration and heightened glycolysis contributes to colitis pathology by activating acid-sensing receptors such as GPR68, a proton-sensing GPCR expressed on immune and stromal cells. Single-cell RNAseq analysis revealed GPR68 is also expressed in colonic sensory neurons, prompting us to investigate its role in acid-induced colonic nociception.

METHODS: Expression of GPR68 in colonic nociceptors and tissue from people with colitis was confirmed by in silico analysis of our RNAseq databases. Its contribution to disease activity was assessed using the acute dextran sulphate sodium (DSS) model of colitis. Acid-evoked sensory signalling was evaluated via colonic afferent recordings and Ca2+ imaging in DRG neurons from wild-type and GPR68-/- mice, supported by pharmacological studies using Ogerin (a GPR68 positive allosteric modulator) and Ogremorphin (a GPR68 antagonist).

RESULTS: RNAseq analysis showed GPR68 is robustly expressed in Trpv1+ colonic nociceptors and upregulated in tissue from people with inflammatory bowel disease, consistent with reduced disease activity in DSS-treated GPR68-/- mice. Genetic deletion of GPR68 abolished colonic afferent responses to acid, which were also attenuated by Ogremorphin and enhanced by Ogerin. In Ca2+-free buffer, DRG neurons from GPR68-/- mice or those pre-treated with Ogremorphin showed significantly reduced acid-evoked intracellular Ca2+ responses. By contrast the colonic afferent and DRG Ca2+ response (in Ca2+-containing buffer) to capsaicin was comparable between tissue from wild-type and GPR68-/- mice highlighting the involvement of divergent proton-dependent cellular signalling cascades.

CONCLUSIONS: These findings identify GPR68 as a key mediator of acid-induced colonic nociception and highlight its potential as a therapeutic target for the treatment of pain in colitis.

PMID:41197770 | DOI:10.1016/j.jcmgh.2025.101671

Nature. 2025 Nov 5. doi: 10.1038/s41586-025-09684-7. Online ahead of print.

ABSTRACT

Breast cancer is the leading cause of cancer-related death in women worldwide1. Here, in the Breast Cancer-Anti-Progestin Prevention Study 1 (BC-APPS1; NCT02408770 ), we assessed whether progesterone receptor antagonism with ulipristal acetate for 12 weeks reduces surrogate markers of breast cancer risk in 24 premenopausal women. We used multilayered OMICs and live-cell approaches as readouts for molecular features alongside clinical imaging and tissue micromechanics correlates. Ulipristal acetate reduced epithelial proliferation (Ki67) and the proportion, proliferation and colony formation capacity of luminal progenitor cells, the putative cell of origin of aggressive breast cancers2. MRI scans showed reduction in fibroglandular volume with treatment, whereas single-cell RNA sequencing, proteomics, histology and atomic force microscopy identified extracellular matrix remodelling with reduced collagen organization and tissue stiffness. Collagen VI was the most significantly downregulated protein after ulipristal acetate treatment, and we uncovered an unanticipated spatial association between collagen VI and SOX9high luminal progenitor cell localization, establishing a link between collagen organization and luminal progenitor activity. Culture of primary human breast epithelial cells in a stiff environment increased luminal progenitor activity, which was antagonized by anti-progestin therapy, strengthening this mechanistic link. This study offers a template for biologically informed early-phase therapeutic cancer prevention trials and demonstrates the potential for premenopausal breast cancer prevention with progesterone receptor antagonists through stromal remodelling and luminal progenitor suppression.

PMID:41193807 | DOI:10.1038/s41586-025-09684-7