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Here the authors engineer a bispecific antibody (Ab) for HIV-1 by combining a gp41 N-heptad repeat targeting Ab with a CD4 binding Ab. Prepositioning via CD4 binding results in high neutralization breadth and potency, and experiments in HIV infected humanized male mice show reduction of viral load.

A wearable device measures parenchymal resistance and its dynamic relationship with sleep MRI measures of glymphatic function, EEG features and cardiovascular parameters in humans.

In this work, we combine LEDGINs with BRD4 modulator ZL0580 to achieve a functional HIV cure. This approach silences the virus by retargeting viral integration into silent chromatin and blocking enhancers, offering a powerful combination strategy to block-and-lock HIV.

In a context of increasing resistance of bacteria to current antibiotic treatment, authors present a newly identified bacterial target, with its inhibition leading to a reduction in bacterial load following infection by Gram negative bacteria, as well as a decrease in bacterial resistance to known antibiotics.

The heme degradation enzyme biliverdin IXβ reductase (BLVRB) is implicated in a redox-regulated thrombopoietic pathway. Here, the authors validate BLVRB as a cellular target by generating an orally-available small molecule inhibitor that retains platelet-enhancing functions that are mechanistically distinct from thrombopoietin receptor-targeted mimetics.

Tummino et al. dock 74 million molecules against the human cannabinoid-1 receptor to find uM ligands. Optimization led to a nM agonist conferring analgesia with reduced side effects in mice, highlighting its potential as a pain therapeutic and the promise of a structure-based approach.

The SARS-CoV-2 3CL main protease (3CL M^pro) is a chymotrypsin-like protease that facilitates the production of non-structural proteins, which are essential for viral replication and is therefore of great interest as a drug target. Here, the authors present the 2.30 Å room temperature crystal structure of ligand-free 3CL M^pro and compare it with the earlier determined low-temperature ligand-free and inhibitor-bound crystal structures.

Robust bioanalytical and modeling methods are needed for covalent drug discovery. Here, the authors demonstrate a mass spectrometry (MS) assay to measure target engagement of any drug-target protein complex, a universal PK/PD model for covalent drugs, and a decision tree to guide research.

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.

Aryl hydrocarbon receptor (AHR) is an emerging immune-related drug target. Here, the authors report the crystal structures of AHR with six agonists bound, revealing the molecular mechanisms of diverse ligand binding and allosteric activation of AHR.

Finding new drug targets may open up a way to combat microbial infections. In this work, authors present the molecular basis for the dual-function regulator MexL as a target to control the virulence and pathogenesis of opportunistic pathogen Pseudomonas aeruginosa.

Structural and cellular assays and molecular dynamics simulations reveal the mechanism of action of γ-glutamyl carboxylase, which involves cholesterol and vitamin K.

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

Tecovirimat forces dimerization of the poxvirus phospholipase F13 blocking virus spread. Clinical monkeypox virus strains resistant to tecovirimat show mutations in the F13 dimer interface.

The development of a first-in-class non-covalent small-molecule inhibitor of SARS-CoV-2 replication that targets the viral guanine-N7 methyltransferase NSP14 is reported.

A key challenge is to find/re-purpose approved drugs that could be used in humans to induce autophagy-associated clearance of neurodegenerative proteins. Here, authors demonstrate that felodipine, an anti-hypertensive drug, can induce autophagy and clear a variety of aggregated neurodegenerative disease-associated proteins in mouse brains at plasma concentrations similar to those that would be seen in humans taking the drug.

The HIV protease inhibitor ritonavir targets the calcium-inducing ___domain (CID) of CD95 to block interactions with PLCγ1. Peptidomimetics targeting the CD95 CID prevents accumulation of inflammatory Th17 cells observed in systemic lupus erythematosus.

Apolipoprotein L1 genetic variants contribute to a subtype of proteinuric kidney disease referred to as APOL1-mediated kidney disease (AMKD). Here the authors report the discovery and characterization of potent and selective APOL1 ion channel inhibitors for the potential treatment of AMKD.

Expression of VIM-2 leads to physiological trade-offs for bacterial pathogens that can be exploited to treat infections caused by multidrug-resistant bacteria.

Small molecule probes used to trigger hypoxic response by activating hypoxia inducible factors (HIFs) often lack specificity. Here the authors report a potent small molecule inhibitor that induces hypoxic response by blocking VHL:HIF interactions, providing a selective route to probe hypoxic signalling.

Cellular target engagement technologies enable quantification of intracellular drug binding, but the simultaneous assessment of drug-associated phenotypes is challenging. Here, the authors develop CeTEAM (cellular target engagement by accumulation of mutant), a platform that can simultaneously evaluate drug-target interactions and phenotypic responses for holistic assessment of drug pharmacology using conditionally stabilized drug biosensors.

Holo-acyl carrier protein synthase (AcpS) is an enzyme that catalyses the first step in lipid synthesis and is essential for bacterial survival, but no current antibiotics targeting AcpS are known. Here, the authors use computer-aided drug design to develop a structurally unique antibiotic family targeting AcpS.

A structure-guided fragment screen identified a compound, which interacts with a ligand-binding site of unknown function in eukaryotic initiation factor 4E (eIF4E). X-ray crystallography was used to characterise binding and target engagment was shown in cells.

This study presents a method that enhances compound bioactivity modeling by integrating diverse data types, enabling cost-effective training data generation. In experimental testing, the best model achieves a 40% hit rate and a negative predictive value of 78%.

Toll-like receptors are key mediators of immune responses, but gaps remain in understanding their signalling. Here, the authors introduce an optical biosensor assay to detect real-time TLR activation and signalling dynamics, uncovering signalling signatures that may aid future drug design.

This study reports adhibin, a synthetic carbazole that suppresses the migratory and adhesive properties of cancer cells by a mechanism of targeted RhoGAP class-IX myosin inhibition and selective RhoGTPase interference, both translating into migrastatic activity, opening other perspectives in cancer therapy and basic research.

Fungal infections are severely underestimated as a cause of mortality, and alternative drugs are urgently needed. Here, Schaefer et al. show that a synthetic polymer mimicking defensins shows different, but synergistic activity with known antifungals.

Protein-protein interactions are central in cell metabolism but research tools for their characterization are missing. Here, the authors introduce strategies for the discovery of nanobodies that modulate the SOS1•RAS complex formation.

Here, Xin Pan and colleagues found that activation of thyroid hormone receptor-β is necessary for alveolar epithelial cell differentiation during lung repair and regeneration, and confirmed a specific agonist and molecular targets for fibrosis therapy.

Sialin transports multiple substrates including sialic acid out of lysosomes, and neurotransmitters into synaptic vesicles. This study reports the cryo-EM structures of Sialin in multiple states revealing its transport and pH-sensing mechanisms.

In this phase 1 trial, treatment of patients with ER⁺HER2⁻ metastatic breast cancer with a selective catalytic inhibitor of the lysine acetyltransferase KAT6 shows a manageable safety profile and encouraging preliminary clinical efficacy.

Development of a paralog-hopping approach leveraging chemical proteomic data on covalently liganded cysteines revealed an allosteric pocket shared by cysteine-containing and cysteine-less paralogous cyclin E proteins.

The pore-forming toxin pneumolysin is responsible for the high mortality seen in pneumococcal infections unresponsive to antibiotics. In this work, authors report a small molecule inhibitor targeting pneumolysin and related ones as an anti-virulence strategy protecting human cells during infection.

Two small-molecule drugs, risdiplam and branaplam, have been developed for treating spinal muscular atrophy. Here the authors develop quantitative modeling methods for the sequence-specific and concentration-dependent effects of these and other splice-modifying drugs.

Wenzell et al. developed a massively parallel screening platform to interrogate the sensitivity of signal peptides (SPs) to Sec61 inhibitors. The platform revealed how distinct inhibitors achieve sequence-dependent SP discrimination.

Hybrids of macrolides and quinolones, called macrolones, can overcome macrolide-induced resistance through new interactions between the quinolone moiety and the ribosome and can concurrently inhibit both ribosome and DNA gyrase targets.

Wang et al. report on an inhibitor of the lysine methyltransferase KMT9 with cellular activity. The inhibitor blocks proliferation of androgen-resistant prostate cancer cells, opening therapeutics avenues to treat this type of cancer.

Here authors aim to understand the 5-HT_2AR coupling signature in response to different signaling probes and their physiological impacts using computational modeling, in vitro and in vivo experiments, and analysis of human brain tissue.