Trends in pharmacological sciences最新文献

Small cell lung cancer (SCLC) progression relies on neuronal activity, yet the mechanisms remain unclear. Two recent studies by Savchuk et al. and Sakthivelu et al. reveal that SCLC co-opts vagal and sympathetic inputs and forms glutamatergic or GABAergic synapse-like connections with neurons, uncovering direct neuron-tumor crosstalk as a key driver of malignancy and a potential therapeutic vulnerability.

Sterile alpha and TIR motif-containing protein 1 (SARM1),is a central enzyme that drives programmed axon degeneration and has gathered significant interest as a therapeutic target. Despite preclinical development of inhibitory therapeutic approaches, clear evidence of the role of SARM1 in human neurodegeneration had been missing until recently. New discoveries demonstrate SARM1 involvement in widespread human neurodegenerative processes. Advances in understanding the mechanism of action of SARM1 have revealed key properties for developing the next generation of SARM1 inhibitors for neuroprotection. Unexpectedly, recent discoveries of pyridine-derived specific SARM1 activators have expanded the therapeutic possibilities for SARM1 beyond neuroprotection to include neuroablation. In this review, we discuss evidence linking SARM1 to human disease and the current challenges to developing safe and effective inhibitors. We also review the emerging field of SARM1 activators and their potential for the development of highly selective neuroablative therapeutics.

Cancer cells alter metabolic programs to support uncontrolled growth and proliferation. A new study from Scott and colleagues directly examined tumor metabolism in glioblastoma patients and discovered increased import of the amino acid serine. Excitingly, limiting serine uptake enhanced the effectiveness of chemoradiation in preclinical models of glioblastoma.

Psilocybin, a serotonergic psychedelic, is gaining attention for its rapid and sustained therapeutic effects in depression and other hard-to-treat neuropsychiatric conditions, potentially through its capacity to enhance neuronal plasticity. While its neuroplastic and therapeutic effects are commonly attributed to serotonin 2A (5-HT_2A) receptor activation, emerging evidence reveals a more nuanced pharmacological profile involving multiple serotonin receptor subtypes and nonserotonergic targets such as TrkB. This review integrates current findings on the molecular interactome of psilocin (psilocybin active metabolite), emphasizing receptor selectivity, biased agonism, and intracellular receptor localization. Together, these insights offer a refined framework for understanding psilocybin's enduring effects and guiding the development of next-generation neuroplastogens with improved specificity and safety.

Metabolic derangements, particularly obesity and post-transplant diabetes mellitus, remain major challenges in solid organ transplantation, contributing to graft dysfunction and increased morbidity. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as promising agents due to their glucose-lowering, weight-reducing, and cardiorenal protective effects. Accumulating evidence supports their efficacy in improving glycemic control, reducing body weight, and potentially enhancing graft and patient survival across diverse transplant populations. Notably, GLP-1RAs exhibit a favorable safety profile, with minimal risk of drug interactions or rejection. Early data also suggest immunomodulatory and anti-inflammatory benefits. Moreover, newer dual and triple incretin agonists offer enhanced metabolic efficacy, potentially extending these benefits further. While long-term outcomes remain under investigation, GLP-1RAs represent a compelling therapeutic option that may reshape metabolic management paradigms in both pre- and post-transplant care.

B7-H3 (CD276), an orphan member of the B7 family, is an immune checkpoint ligand and a tumor-associated antigen. Recent developments regarding dimerization, glycosylation, expression regulation, and effects on cell metabolism are emerging, along with a newfound role as a regulator of obesity. As a therapeutic target, ongoing clinical trials with antibody-drug conjugates (ADCs) and chimeric antigen receptor (CAR) immune cells targeting B7-H3 have proved to be safe and effective across different human cancer types. Multiple new preclinical studies have also provided novel treatments targeting B7-H3, including TMIGD2 optimized potent/persistent (TOP) CAR cells, bispecific ADCs, CAR-natural killer (NK) cells, and T cell engagers. In this review we highlight the diverse emerging functions of B7-H3 in both physiological and pathological conditions, and discuss new therapies targeting this molecule.

Allosteric potentiation of G protein-coupled receptor (GPCR) signaling provides new opportunities for therapeutic discovery. Recently, the laboratory of Peter Chidiac has reported strong allosteric potentiation of numerous GPCRs by extracellular ATP, with the minimal pharmacophore represented by sugar monophosphates. This discovery potentially aids the development of novel allosteric modulators for numerous therapeutically attractive GPCRs.

The cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING) pathway, a crucial component of host innate immunity, detects aberrant DNA during viral infection. It is well established that cGAS-STING signaling activation during viral infections is often insufficient for complete viral clearance, indicating that numerous viruses have evolved countermeasures against this major pathway. However, the precise mechanisms by which viruses antagonize the cGAS-STING pathway to ensure intracellular survival remain incompletely understood. This review synthesizes recent progress in elucidating how diverse RNA and DNA viruses disrupt various stages of cGAS-STING pathway activation. These mechanistic insights into viral evasion have significant implications for the development of targeted therapeutic interventions. Specifically, the precise delivery of small-molecule or peptide-based drugs designed to counteract viral evasion proteins represents a promising direction for future antiviral therapy.