Trends in pharmacological sciences最新文献

Neuronal networks rely on a balance between the activity of excitatory and inhibitory neurons, each having distinct roles in regulating the flow of activity across brain circuits and signal processing. Recent work by Selten et al. uncovers how parvalbumin (PV)-expressing interneurons adjust their inhibitory inputs in response to activity changes, revealing a neuropeptide-based mechanism.

An effective therapeutic strategy to treat oncogenic Wnt signaling in the context of colorectal cancer (CRC) remains elusive. A new study from Cho and colleagues describes a novel mechanistic link between the loss of canonical adenomatous polyposis coli (APC) function, membrane cholesterol, and an innovative drug target to specifically suppress the cholesterol-Dvl-β-catenin signaling axis.

Osteoarthritis (OA) is a leading cause of disability worldwide and is characterized by cartilage loss, inflammation, and pain. Despite advances, effective disease-modifying treatments are lacking. Emerging evidence highlights ion channels as key regulators of OA that affect chondrocyte survival, mechanotransduction, inflammation, and nociception. This review discusses ion channel families - including sodium, potassium, TRP, Piezo, acid-sensing, and chloride channels, as well as ligand-gated receptors - and their roles in OA progression. We explore preclinical and clinical advances in ion channel-targeted therapies, such as small-molecule inhibitors, biologics, and gene therapies, as well as repurposing of existing drugs for symptom relief and disease modification. Challenges in selective targeting, pharmacological and drug delivery strategies, and patient stratification are also addressed. Continued research on ion channel biology is essential for developing targeted OA therapies to enable precision medicine via site-specific strategies that minimize systemic side effects.

Despite the availability of effective hormonal contraceptive methods, nearly half of pregnancies worldwide remain unintended, highlighting the urgent need for innovative, nonhormonal options. Prostate-specific antigen (PSA) is a biomarker for prostate cancer and is well established for its role in liquefying semen by hydrolyzing gel-forming proteins. Liquefaction is essential for sperm motility and fertilization, making PSA inhibition a prime candidate for novel contraceptive strategies. Advances in prostate cancer research have led to the development of PSA inhibitors for cancer therapeutic purposes, including drugs that suppress PSA activity or selectively kill PSA-expressing cells. PSA presents a unique target as it is produced in men and acts in women, making it a promising contraceptive strategy for both sexes. This opinion explores the potential adaptation of existing PSA inhibitors from the oncology field for contraceptive applications. It also highlights emerging strategies to identify effective PSA-targeted contraceptive candidates, opening new avenues for next-generation nonhormonal contraception for men and women.

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.

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.

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).