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Arginine addiction induced by argininosuccinate synthase (ASSN1) deficiency has been exploited to treat ASS1-deficient cancers. Here, the authors show an alternative therapeutic approach where ASS1 activity is increased by the pesticide spinosyn A and is shown to inhibit breast cancer cell proliferation.

Yeast surface display technology enables real-time monitoring and effective screening of libraries of millions of disulfide-cyclised peptides against diverse protein targets. Selected ligands are characterised rapidly and quantitatively without the need for chemical synthesis and purification.

The validation of inhibitors targeting PurF, a novel drug target for tuberculosis drug discovery, is described.

The identification of cellular targets for natural products that potently inhibit the growth of cancer cell lines implicates oxysterol-binding proteins in the growth of cancer cells. These natural products, termed ORPphilins, also affect sphingomyelin biosynthesis.

Dihydroxyacid dehydratase (DHAD) is an essential enzyme for the synthesis of branched-chain amino acids in plants. Here, the authors rationally design a range of DHAD inhibitors as herbicides and present the crystal structure of a lead compound in complex with Arabidopsis DHAD.

A synthetic route to GB18, an alkaloid from the bark of hallucinogenic Galbulimima sp., is developed, enabling its identification as an antagonist of κ- and μ-opioid receptors.

Many drugs discovered by serendipity possess the ability to react with cysteine residues on target proteins. Here the authors report a large-scale chemoproteomic analysis to define proteome-wide ligandability maps of 70 drugs with diverse cysteine-reactive chemotypes in native biological systems.

Proton pump inhibitors (PPIs) are prodrugs that are activated by protonation in the highly acidic environment of the stomach lining. Now, coordination of PPIs to protein-bound zinc ions is revealed as another pathway to PPI activation. Acting as a Lewis acid, the zinc ion facilitates conjugation of the drug to zinc-coordinating cysteine residues.

Highly structured RNA regions in SARS-CoV-2 serve as potential drug targets. Here the authors identified a class of small molecules binding to the 5’ UTR of the SARS-CoV-2 RNA genome. Using cgSHAPE-seq, they pinpointed a bulged G as the binding site and developed RNA-degrading chimeras that inhibit viral replication.

Uechi et al. found that a small-molecule lipoamide dissolves stress granules (SGs) by targeting SFPQ, a redox-sensitive disordered SG protein, alleviating pathological phenotypes caused by amyotrophic lateral sclerosis-associated FUS and TDP-43 mutants.

Inhibition of a cardiac stroma-enriched mechanosensor, SRC—in concert with suppression of the TGFβ pathway—potentiates the reversal of fibroblast activation and alleviates contractile dysfunction in fibrotic hearts.

Dynamic gene expression is crucial for coordinating diverse cellular activities, but challenging to modulate with high spatiotemporal precision. Now, a photoswitchable DNA structure-specific, small-molecule ligand enables reversible, light-controlled regulation of gene expression and cell proliferation in live cells.

Identifying therapeutic targets is challenging, especially for orphan diseases. Here, the authors integrate GWAS and TWAS with machine learning methods to predict therapeutic targets for various diseases and demonstrate the usefulness in practice.

Obesity is a significant health risk, and current treatments are inadequate. This study reveals that AA005, an annonaceous acetogenin mimic, targets mitochondrial HADHA in adipose tissue to boost thermogenesis via the UCP1 pathway, providing a promising new strategy for obesity treatment.

Here, the authors analyzed 2923 plasma proteins through prospective cohort and genetic analyses, identifying IL12B, CD6, MXRA8, CXCL9, IFNG, CCN3, RSPO3, and IL18 as prioritized potential therapeutic targets for inflammatory bowel disease, offering insights into its mechanisms and treatment.

The important tuberculosis drug pyrazinamide (PZA) is converted to its active form pyrazinoic acid (POA) in Mycobacterium tuberculosis (Mtb). Here the authors identify the pantothenate biosynthesis pathway enzyme aspartate decarboxylase (PanD) as the target of PZA and determine the POA bound Mtb PanD crystal structure.

The authors developed a small molecule targeting the circadian regulator BMAL1, enabling dose-dependent modulation of gene expression for circadian-controlled genes and downregulation of inflammatory pathways in macrophages.

A new lasso peptide antibiotic exhibits broad-spectrum activity against Gram-negative and Gram-positive bacteria by interfering with bacterial protein synthesis, is unaffected by common resistance mechanisms and shows no toxicity towards human cells.

High-throughput screening and hit optimization have led to the development of a small molecule, CIM-834, that targets the SARS-CoV-2 membrane protein and blocks assembly of the virus.

In a broad cross-tissue analysis, the authors show that a receptor called EDA2R steadily increases with age in both humans and animal models, and becomes even more active in conditions like obesity and diabetes, intensifying inflammation-like processes in muscle cells.

Yang and colleagues present a small-molecule inhibitor for ADAR1 and show that its use is therapeutically beneficial in the context of prostate cancer.

The global regulator PhoP plays crucial roles in bacterial pathogenicity. Shi et al. report four cryo-EM structures of PhoP-dependent transcription activation and repression complexes, revealing dual transcription regulation mechanisms of PhoP.

Targeting cancer stem cells (CSCs) has great potential in anti-cancer treatment. Here this group reports the role of antibiotic Nifuroxazide as a potent anti-CSC compound and fabricates it into an anti-breast CSC prodrug using click chemistry strategy.

PELO–HBS1L and SKI complexes in the human mRNA quality control pathway exhibit a synthetic lethal interaction and may represent novel targets for the development of cancer therapies.

This study refines ibrutinib’s target landscape by resolving drug targets while accounting for functional proteoform groups, identifying off-targets linked to immunomodulation and cellular processes and identifying variability in CLL patient responses, establishing a framework to understand drug interactions in precision medicine.

Alpha-synuclein (aSyn) aggregation is implicated in Parkinson’s disease, yet the molecular mechanisms, particularly involving lipid interactions, remain poorly understood. Here, the authors develop a mathematical model incorporating nucleation-conversion-polymerization processes to elucidate aggregation dynamics upon aSyn-lipid interaction, offering insights into therapeutic strategies and advancing quantitative systems pharmacology for neurodegenerative diseases.

Protein–protein interactions specific to 11 individual tissues are presented in a comprehensive resource.

Ferroptosis is a promising therapeutic target for a variety of diseases, but a majority of known ferroptosis inhibitors belong to either antioxidants or iron chelators. Here, the authors discover a new non-classical small molecule inhibitor that is a PHB2 binder and show it ameliorates liver damage in an acute liver injury model.

Plasmodium falciparum Snf2L is an ISWI-related ATPase that actively repositions P. falciparum nucleosomes in vivo.

An atlas of the associations between the use of GLP-1 receptor agonists (GLP-1RAs) and 175 health outcomes reports the effectiveness and risks of GLP-1RAs compared with other antihyperglycemic medications, such as sulfonylureas, DPP4 inhibitors and SGLT2 inhibitors.

UM171 promotes corepressor degradation by acting as a molecular glue to induce KBTBD4–HDAC1/2 interactions with the help of inositol hexakisphosphate.

Bestrophin anion channels are critical for the health of eyes. Here, authors identify multiple bestrophin activators including glutamate and γ-aminobutyric acid.

Here the authors discover that furanodienone (FDN), a small molecule derived from ginger, exhibits PXR agonist activity selective for the intestine and show that when FDN is administered orally in pharmacological doses ameliorates induced colitis in male mice.

Harrington et al report their discovery of Nemacol, which is a small molecule inhibitor of the vesicular acetylcholine transporter (VAChT). VAChT loads synaptic vesicles with acetylcholine and is a key point of vulnerability in animals. Harrington et al show that Nemacol has nematode selectivity and potential utility against nematode parasites.

Photocages are crucial for applications in bioimaging and controlled drug release, yet expanding their structural diversity remains a challenge. Here, the authors introduce a class of hydrazone-based photocages that release fluorescent aldehydes upon light exposure, enabling precise sub-organelle imaging and efficient light-controlled drug delivery, with significant implications for biomedical research.

Late-stage acute liver failure (ALF) has limited therapies. The authors show that the bioactive compound SCM-198 extends the ALF treatment window from 3 to 24 hours in mice by selectively targeting the identified AdipoR2-CaM-CaMKII-NOS3-NO axis.

Avocado fatty alcohols/acetates (AFAs) are effective against parasitic nematodes, including drug resistant strains, and show safety in mammalian cells. AFAs target lipid metabolism, offering the potential for new anthelmintic treatment pathways.

In this study, Wrigth et al. use structural, medicinal chemistry, and behavioral approaches to examine how equilibrative nucleoside transporter subtype 1 (ENT1) exerts its functions; and their findings reveal ENT1 as a potential target for analgesia.

The authors used deep metric learning to characterize 650 neuroactive compounds by zebrafish behavioral profiles. After redesigning a large screen to overcome AI/ML shortcut learning, zebrafish behavioral similarity found compounds acting on the same human receptors as structurally dissimilar drugs.

Here, the authors identify genes and drug targets that show immune cell-specific and activation time point-specific effects on type 2 diabetes and coronary heart disease and find strong immune-to-metabolic disease connections.

Identification of a broadly therapeutic antibody h1A6.2 against enteroviruses, which mimics the entry receptor SCARB2 and triggers monocyte/macrophage-dependent Fc effector functions in mice.

Payton et al. develop small-molecule inhibitors of kinesin KIF18A able to selectively kill cancer cells with high chromosomal instability and demonstrate that the inhibitors are therapeutically beneficial in cancer patient-derived in vivo models.

Encoded Library Technology (ELT) has streamlined the identification of chemical ligands for protein targets in drug discovery. Here, the authors optimize the ELT approach to screen multiple proteins in parallel and identify promising targets and antibacterial compounds forS. aureus, A. baumannii and M. tuberculosis.