Trends in pharmacological sciences最新文献

Viruses are likely to cause future pandemics due to their inherent ability to evolve and spread rapidly, with limited treatment options. Engineered multivalent decoy receptors (EMDRs) offer a broad-spectrum alternative treatment option. We propose and evaluate EMDRs and their delivery methods to guide future efforts toward pandemic preparedness.

Adjuvants are substances used in vaccines to boost antigen-specific immune responses. Aluminum salts (alum) were the first adjuvant approved for human use. Unfortunately, they mainly induce antibody responses and are ineffective at eliciting strong T cell immunity, limiting their use in cancer vaccines. Recent advances reveal the mechanisms of various metal ions in modulating immune signaling. By integrating the synergistic immunomodulation of metal ion pairings with nanotechnology, bimetallic nanoadjuvants (BMNAs) are revolutionizing cancer vaccine. This approach overcomes the limitation of conventional single metal adjuvants by enabling multiplexed immune activation, leading to robust T cell responses for tumor control. This review highlights the immunological mechanisms of metal ions, the rationale behind their pairing in BMNAs, and current challenges for clinical translation.

Non-muscle myosin II (NMII) comprises a family of cytoplasmic motors with important roles in both normal biology and disease. In this forum article we describe recent developments that validate NMII as a therapeutic target, and we illustrate how this validation can identify novel and translationally viable approaches to treat a variety of diseases.

Chronic pain remains inadequately managed, partly because of insufficient consideration of neuroimmune interactions in therapeutic design and a continued reliance on single-target strategies ill-suited to its complexity. Multitarget-directed ligands that modulate the non-neuronal microenvironment of neuronal pain pathways show promise, supported by encouraging preclinical data and initial clinical findings.

Cancer immunotherapy has revolutionized oncology, but its full potential remains constrained by treatment resistance, limited durability, immune evasion, and systemic toxicity. Overcoming these obstacles requires innovative strategies for remote and targeted immunomodulation. Opsin-free optogenetics has emerged as a powerful tool in cancer immunotherapy because its versatility and photoactivation kinetics align with the timescale of immune cell signaling, and it has given rise to the subfield of optogenetic immunoengineering. This review explores design strategies and key applications of optogenetic immunoengineering, focusing on the opsin-free optogenetic toolkit in immunotherapy and its ability to modulate the cancer-immunity cycle which is required for amplifying and sustaining antitumor responses. By enabling precise regulation of both innate and adaptive immunity, as demonstrated in recent preclinical studies, optogenetic immunoengineering holds great promise for advancing next-generation precision medicine.

Transcytosis across the blood-brain barrier (BBB) enables systemically administered large therapeutics to reach the brain parenchyma, but their fate in the parenchyma ultimately governs their therapeutic effect. Recent studies show that brain parenchymal cell uptake, internalization kinetics, reuptake at the BBB, and diffusion in the brain parenchyma shape the distribution and retention of therapeutics. Target engagement further influences their behavior beyond the BBB. These insights have prompted new strategies to enhance their distribution, retention, and target engagement. These include the selection of transport targets with favorable trafficking properties, the use of anchoring proteins, and modeling-based optimization. This opinion highlights emerging understanding of the fate of therapeutics in the brain parenchyma and outlines strategies to optimize this fate.

The escalating threat of antimicrobial resistance demands innovative therapeutic strategies beyond classical targets. Recent insights into the mechanisms of bacterial iron acquisition - ranging from siderophores and heme uptake to ferrous iron transport - have enabled new approaches to impair pathogen growth and virulence. These pathways are increasingly being harnessed for therapeutic gain. Emerging strategies include next-generation iron chelators with improved specificity and reduced toxicity, gallium-based iron mimics that disrupt redox metabolism, and siderophore-drug conjugates that hijack bacterial uptake systems for targeted delivery. In parallel, antivirulence agents such as hemolysin inhibitors are promising resistance-sparing alternatives by targeting iron-driven pathogenesis. In this review we highlight these advances and emphasize the potential of host-mediated iron sequestration and bio-inspired nanotechnologies to strengthen nutritional immunity and guide future antimicrobial strategies.

Biased G-protein-coupled receptor (GPCR) signaling is reshaping drug discovery by enabling pathway-selective drug action. Recent work by Motso et al. identified GPCR kinase 2 (GRK2) as a non-canonical transducer, independent of G proteins or β-arrestins, redefining the biased signaling landscape and highlighting GRK2 as a novel therapeutic target for selective modulation of GPCR-driven metabolic responses.

Regulatory T cells (Tregs) play a pivotal role in maintaining immune tolerance and sustaining immunological homeostasis. Emerging evidence indicates that Treg characteristics and functional alterations can significantly contribute to the pathogenesis of autoimmune diseases including type 1 diabetes mellitus (T1DM). Notably, recent studies have established a positive correlation between diminished numbers of Tregs and the onset of T1DM. Although targeting Tregs has emerged as an attractive therapeutic strategy for T1DM, the heterogeneity and mechanistic complexities of Tregs remain largely unexplored and limit clinical success. We explore the dynamic alterations of Treg frequencies and phenotypes, and discuss their regulatory mechanisms throughout T1DM progression. Furthermore, we provide an overview of preclinical studies and clinical trials targeting Tregs in T1DM. By addressing translational challenges and current limitations in clinical efficacy, the ultimate aim is to develop innovative immunotherapeutic interventions for T1DM.

G proteins, members of the GTPase superfamily, are central mediators of signal transduction downstream of G protein-coupled receptors (GPCRs). Despite their critical roles in normal physiology and the high intrinsic affinity for endogenous ligands, G proteins have traditionally been considered 'undruggable'. Recent advances have led to the development of small molecules and peptides targeting wild-type (WT) G proteins; however, none have yet progressed to clinical application. By contrast, somatic and germline mutations in G proteins have been increasingly implicated in oncogenesis and neurodevelopmental disorders. Thus, targeting mutant G proteins represents a promising therapeutic strategy, offering the potential for selective intervention while sparing normal signaling. In this review, we provide an overview of known G protein modulators and pathogenic mutations recently reported in the literature, and discuss emerging opportunities for therapeutic targeting of mutant G proteins.