Trends in pharmacological sciences最新文献

Efferocytosis, the clearance of apoptotic cells (ACs) by phagocytes, is crucial for bone homeostasis and immune balance. This tightly regulated process depends on molecular markers such as phosphatidylserine on ACs and MERTK on phagocytes. In the bone microenvironment, multiple cell types participate in efferocytosis, including osteal macrophages, mesenchymal stem cells, osteoblasts, and osteoclasts, directly influencing bone remodeling and immune responses. Impaired efferocytosis disrupts bone turnover, exacerbates inflammation, and contributes to inflammatory bone diseases. Despite its recognized importance, the precise mechanisms regulating efferocytosis in osteoimmunology remain underexplored, including specific signaling pathways, cell-specific interactions, and therapeutic applications. Recent advances highlight the therapeutic potential of targeting efferocytosis using modalities and biomaterial-based strategies. This review systematically examines the role of efferocytosis in osteoimmunology, discusses key challenges in its therapeutic translation, and explores emerging strategies to optimize efferocytosis-based interventions for inflammatory bone disorders.

The NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is a megadalton complex implicated in numerous inflammation-driven diseases including COVID-19, Alzheimer's disease, and gout. Although past efforts have focused on inhibiting IL-1β downstream of NLRP3 activation using drugs such as canakinumab, no FDA-approved NLRP3-targeted inhibitors are currently available. MCC950, a direct NLRP3 inhibitor, showed promise but exhibited off-target effects. Recent research has focused on optimizing the sulfonylurea-based MCC950 scaffold by leveraging recent structural and medicinal chemistry insights into the NLRP3 nucleotide-binding and oligomerization (NACHT) domain to improve solubility and clinical efficacy. In addition, oxidized DNA (oxDNA) has emerged as a key inflammasome trigger, and molecules targeting the pyrin domain have shown promise in inhibiting NLRP3 activation. This review discusses the role of NLRP3 in inflammation-related diseases, the status of ongoing clinical trials, and emerging small-molecule therapeutics targeting NLRP3.

The frameshifting element (FSE) comprises a slippery heptanucleotide sequence followed by a downstream RNA structure, such as a pseudoknot or stem-loop. Found in various RNA viruses, FSE regulates viral replication via programmed -1 ribosomal frameshifting (-1 PRF), making it a potential broad-spectrum antiviral target. Advances in RNA structural analysis have elucidated the dynamic conformations and cross-viral diversity of FSE, with the SARS-CoV-2 outbreak further highlighting its role in viral replication. Efforts to develop antiviral drugs targeting FSE have progressed through virtual and phenotypic screening. In this review, we explore the evolution, structure, and function of FSE in coronaviruses, evaluate recent advances in FSE-targeted drug development, and discuss their design advantages, efficacy, and challenges, providing insights for future antiviral strategies.

The identification of neurodegenerative disease (ND) biomarkers in easily accessible body fluids is crucial in the fight against this class of disorders. Brain-derived extracellular vesicles (BDEVs) have gained attention as nanoscale carriers of molecular information and bioactive molecules that reflect the status of their source cells. By crossing the blood-brain barrier (BBB), BDEVs can transfer these biomolecular signatures to peripheral biofluids, setting the scene for their use as ND biomarkers. In this review, we explore the role of BDEVs in liquid biopsy as a promising route for early ND diagnosis, as well as patient stratification and follow-up, with a particular focus on their ability to transport misfolded proteins and protein aggregates, major actors in neurodegeneration development. We also discuss the link between the physicochemical properties of BDEVs and the potential insights gained into NDs, highlighting both challenges and opportunities associated with the use of BDEVs for ND diagnostics.

Binding immunoglobulin protein (BiP) and glucose-regulated protein 94 (Grp94) are endoplasmic reticulum (ER)-localized molecular chaperones that ensure proper protein folding and maintain protein homeostasis. However, overexpression of these chaperones during ER stress can contribute to disease progression in numerous pathologies. Although these chaperones represent promising therapeutic targets, their inhibition has been challenged by gaps in understanding of targetable chaperone features and their complex biology. To overcome these challenges, a new assay has been developed to selectively target BiP, and compounds that exploit subtle conformational changes of Grp94 have been designed. This review summarizes recent advances in elucidating structural and functional dynamics of BiP and Grp94. We explore leveraging this information to develop novel therapeutic interventions. Finally, given the recent advances in computing, we discuss how machine learning methods can be used to accelerate drug discovery efforts.

In a recent report in Nature Communications, Kitai et al. designed a combinational treatment based on targeting the active-state KRAS^G12C-mutant variant that characterizes a substantial subset of non-small-cell lung cancer (NSCLC) cases. The authors highlighted that dual targeting with KRAS^G12C (ON) and mammalian target of rapamycin (mTOR) complex (mTORC)-1-selective inhibition potentially provides a new strategy to overcome drug resistance.

Clustered regularly interspaced short palindromic repeats (CRISPR) tools are revolutionizing the establishment of genotype-phenotype relationships and are transforming cell- and gene-based therapies. In the field of oncology, CRISPR/CRISPR-associated protein 9 (Cas9), Cas12, and Cas13 have advanced the generation of cancer models, the study of tumor evolution, the identification of target genes involved in cancer growth, and the discovery of genes involved in chemosensitivity and resistance. Moreover, preclinical therapeutic strategies employing CRISPR/Cas have emerged. These include the generation of chimeric antigen receptor T (CAR-T) cells and engineered immune cells, and the use of precision anticancer gene-editing agents to inactivate driver oncogenes, suppress tumor support genes, and cull cancer cells in response to genetic circuit output. This review summarizes the collective impact that CRISPR technology has had on basic and applied cancer research, and highlights the promises and challenges facing its clinical translation.

Venom peptides specialized in modulating intracellular calcium ([Ca²⁺]_i) offer a treasure trove of pharmacological properties to regulate aberrant Ca²⁺ homeostasis in disease. Combined with emerging advances across peptide optimization, disease models, and functional bioassays, these venom peptides could unlock new therapies restoring Ca²⁺ homeostasis. In this opinion, we explore the pharmacology of venom peptides modulating [Ca²⁺]_i signaling along with recent breakthroughs propelling venom peptide-based drug discovery. We predict a transformative era in therapeutic development harnessing venom peptides targeting dysfunctional Ca²⁺ signaling in intractable conditions such as neurodegenerative diseases.

Glioblastoma (GBM) remains a therapeutic challenge due to its heterogeneity and plasticity, which drive treatment resistance, especially when compounded by interactions with the brain microenvironment. Recent preclinical evidence indicates that trifluoperazine (TFP) inhibits treatment-induced malignant reprogramming of tumour cells, potentially helping to reduce tumour plasticity. TFP targets calmodulin, dopamine receptors, and stress-responsive proteins (nuclear protein 1, NUPR1). Through these mechanisms, TFP has been shown to reduce tumour growth, sensitise tumours to chemoradiotherapy, and prolong survival in xenograft animal models. The clinical safety profile of TFP is well known from its use as an antipsychotic, and recent preclinical evidence further indicates that TFP has low toxicity to healthy neurons and glia despite transient functional effects on dopamine receptors. This Opinion explores TFP mechanisms of action and clinical activity to assess its suitability as a repurposed therapeutic option for GBM.