Trends in pharmacological sciences最新文献

Antagonizing the aryl hydrocarbon receptor (AhR) is a highly pertinent pharmacotherapeutic strategy. To overcome the drawbacks of existing AhR antagonists, novel molecules that can selectively target canonical and noncanonical AhR pathways are urgently needed. Recent reports on the structures and functions of cytosolic and nuclear AhR-protein complexes have allowed for understanding structural determinants for intrinsic activity and functional selectivity of AhR ligands. This new information regarding AhR surface interactions has opened new avenues for the development of novel AhR antagonists. Achievable strategies include the negative allosteric modulation of AhR and the disruption of AhR-protein and AhR-DNA interfaces using peptidomimetics or small molecules. Here, we discuss such novel approaches that may lead to new AhR-targeted therapeutics.

Acylations are conserved and dynamic modifications that control various biological processes, including gene transcription and protein biology, and have been tied to diseases, such as cancers. Due to their reversible characteristic, acylations exhibit great therapeutic potential through targeting of their regulatory enzymes and proteins. Recent studies have improved our understanding of the close interplay between acylations and the tumor immune microenvironment (TIME), showing the potential to improve antitumor immune responses via acylation manipulation. Herein, we review the effects of acylations, including acetylation, lactylation, palmitoylation, and some less well-known acylations on cancer immunity, and corresponding therapeutic opportunities. Specifically, we bring into focus diverse roles of different acylation-related enzymes, metabolites, or substrates to provide insights into targeting acylations to increase antitumor immunity and generate broader research enthusiasm.

Conformation-specific antibodies represent powerful tools for targeting pathogenic amyloid aggregates. However, the discovery of aggregate-selective antibodies with drug-like developability properties has been slow, inefficient, and difficult to generalise across different amyloid targets. The Tessier lab has developed a yeast-display screening pipeline that enables conformation-specific antibody discovery against diverse aggregated proteins.

TAR DNA binding protein 43 kD (TDP-43) aggregation is associated with several neurodegenerative diseases and limiting TDP-43 aggregates could offer therapeutic benefit. Recently, Wagner et al. utilized the induced proximity to PML for enhancing TDP-43 solubility under stress. Mechanistically, this strategy triggers a SUMOylation-ubiquitylation cascade on TDP-43 and the compartmentalization of TDP-43 to the promyelocytic leukemia-nuclear bodies (PML-NBs).

Mitochondrial pyruvate carrier (MPC) inhibitors have shown promise as therapeutics for treating several chronic diseases. However, the structure of MPC and the molecular mechanisms by which it interacts with inhibitors have remained unclear, impeding rational drug design. Multiple groups have now independently resolved the structure of the MPC heterodimer.

G protein-coupled receptors (GPCRs) are a large superfamily of receptors critical for mammalian cell-cell communication and a common drug target. A new study has revealed that the human gut microbiome can metabolize GPCR-targeted drugs into both expected and surprising metabolites, with potentially broad implications for the treatment of disease.

Pulmonary arterial hypertension (PAH) is a progressive, life-threatening vasculopathy characterized by sustained vasoconstriction and pathological remodeling of small pulmonary arteries. While current vasodilator therapies improve symptoms and survival, they are not curative and fail to reverse vascular remodeling. Recently, a shift toward disease-modifying strategies has emerged, driven by preclinical advances now entering clinical translation. The approval of sotatercept, the first agent presumed to target vascular remodeling, and the development of seralutinib, an inhaled tyrosine kinase inhibitor (TKI), mark key milestones. In this review, we focus on anti-remodeling therapies that have progressed from preclinical models to clinical trials. These include agents targeting cell cycle regulators, kinase pathways, epigenetic modifiers, bone morphogenetic protein receptor type 2 (BMPR2) signaling, and senescence in pulmonary arterial smooth muscle cells (PASMCs), offering renewed hope for durable PAH treatment.

The orphan G protein-coupled receptor (GPCR) GPR17, whose physiological agonist remains unknown, has emerged as a promising drug target for multiple sclerosis (MS). Blockade of the receptor enables remyelination and may offer a novel therapeutic strategy for MS. Only recently, potent and selective tool compounds for GPR17 have become available, and patents on antagonists have surged, leading to the first clinical candidate, the GPR17 antagonist PTD802, which is to be developed for MS therapy. This may pave the way for further clinical studies exploring additional indications, such as neurodegenerative diseases. The newly determined cryo-electron microscopy (cryo-EM) structure of GPR17 is expected to facilitate future structure-based drug design efforts. This review presents and discusses these latest developments, providing a timely and comprehensive overview to guide future research in the field.

Lymphocyte activation gene-3 (LAG-3) has emerged as a critical immune checkpoint receptor primarily modulating T-cell responses through distinct immune regulatory mechanisms. Recent advances have elucidated LAG-3's complex receptor-ligand interactions, structure-function relationships, and unique signaling pathways. LAG-3 antagonistic antibodies, such as relatlimab approved for melanoma, have shown promising efficacy with favorable toxicity profiles, though only in combinational therapies. While LAG-3's role in oncology continues to expand, it is also gaining recognition as a potential therapeutic target for other disorders. This review highlights recent progress in understanding LAG-3's molecular features, ligand regulation, signaling, and immune modulation mechanisms. Additionally, it explores emerging questions in oncology and the exciting potential of therapies targeting the LAG-3 pathway in autoimmune disease. A deeper understanding of LAG-3's confounding biology and disease relevance would drive the development of novel immunotherapies across broader clinical indications.