The changing landscape of medicinal chemistry optimization www.nature.com/articles/s41... rdcu.be/evaV5 This new article analyses oral drug candidates and their corresponding hit and lead compounds from recent years and from the early 2000s, and discusses the implications of the observed trends

Predicted 1,633 human proteins as potential CRBN molecular glue targets, far broader than expected. Discovered helical G-loops as a new recognition motif. Demonstrated VAV1 can engage CRBN without G-loop structure through molecular surface mimicry. Science: www.science.org/doi/10.1126/...

Prime editor-based high-throughput screening reveals functional synonymous mutations in human cells Nature Biotechnology www.nature.com/articles/s41...

Fully computational design achieves Kemp eliminase efficiency of 12,700 M⁻¹s⁻¹ without experimental optimization. Surpasses previous designs by 2 orders of magnitude. Final variant reaches 10⁵ M⁻¹s⁻¹, matching natural enzyme performance.😲 Nature: www.nature.com/articles/s41...

JNJ-6640: First-in-class PurF inhibitor demonstrates nanomolar bactericidal activity against M. tuberculosis. Targets de novo purine biosynthesis pathway, showing in vivo efficacy in mouse models. Nature: www.nature.com/articles/s41...

R9AP identified as common EBV receptor for both epithelial & B cell infection. R9AP binds directly to viral gH/gL complex, mediating membrane fusion. AMMO1 antibody blocks this interaction, suggesting therapeutic potential. Nature: www.nature.com/articles/s41...

moPepGen: Graph-based algorithm achieves linear-time generation of non-canonical peptides from genomic variants, RNA fusions & circularization. Outperforms existing tools, enabling detection of 53.7% more peptides in cancer proteomes. NatBiotech: www.nature.com/articles/s41...

FRα identified as novel lysosome-trafficking receptor for targeted protein degradation. Polyvalent FRTACs achieve subnanomolar potency against membrane proteins. PD-L1-targeting FRTAC demonstrates robust degradation in vivo & reprograms TME in mice. NatChemBio: www.nature.com/articles/s41...

PSC patients show expanded T & B cell responses against EBV epitopes compared to controls. Analysis of 116M+ health records reveals infectious mononucleosis increases PSC risk (OR=12). This suggests EBV may play a role in autoimmune liver disease pathogenesis NatMed: www.nature.com/articles/s41...

LucaOne: First AI model to unify DNA, RNA & protein language. Trained on 169K+ species, it demonstrates emergent understanding of genetic translation without explicit training. Outperforms specialized tools across multiple tasks. Nature Machine Intelligence: www.nature.com/articles/s42...

"Is taurine an aging biomarker?" Longitudinal data from humans, monkeys, and mice show circulating taurine does not decline with age. High individual variability and context-dependent health links limit its utility as an aging biomarker. Science: www.science.org/doi/10.1126/...

CREM, a transcriptional repressor induced by CAR and IL-15 signaling via the PKA–CREB axis, limits CAR-NK effector function. Genetic ablation enhances anti-tumor activity and resistance to suppression, identifying CREM as a targetable intracellular checkpoint. Nature: www.nature.com/articles/s41...

A blood-based DNA methylation “IC clock” predicts mortality and tracks decline in intrinsic capacity across five domains—cognition, mobility, vitality, sensory, and psychological. Strongly linked to immune aging and lifestyle factors. Nature Aging: www.nature.com/articles/s43...

Exosome-enriched glycoRNAs carry internal GalNAc modifications and resist RNase, suggesting glycosylation marks RNA for export. Disruption of protein glycosylation impairs glycoRNA trafficking. Nature Cell Biology: www.nature.com/articles/s41...

Loss of PD-1 in Treg cells triggers a compensatory coinhibitory network centered on CD30, promoting stronger immune suppression through STAT5 activation and potentially undermining the efficacy of PD-1-based immunotherapy. Nature Immuno: www.nature.com/articles/s41...

n a phase 2 trial, CIS43LS showed durable protection (87.4% efficacy at 40 mg/kg) against submicroscopic Plasmodium infection by qRT-PCR, highlighting mAb-based prophylaxis as a tool for malaria control. Nature Medicine: www.nature.com/articles/s41...

Rentosertib, a first-in-class TNIK inhibitor discovered by generative AI, improved forced vital capacity and showed favorable safety in a phase 2a IPF trial. A milestone for AI-driven drug discovery, linking de novo target identification. Nature Medicine: www.nature.com/articles/s41...

Ketogenic diet or β-hydroxybutyrate administration halts Plasmodium development and protects mice from malaria. Mechanism: NAD depletion and transcriptional repression of virulence genes in the parasite. A metabolic strategy for malaria resistance. Nature metabolism: www.nature.com/articles/s42...

Cysteine depletion drives adipose browning and rapid weight loss via SNS–β3AR signaling, even without UCP1. In obese mice, this triggers 30% weight loss and reverses inflammation. A potential non-canonical path for therapeutic thermogenesis. Nature metabolism: www.nature.com/articles/s42...

HSV-1 counteracts APOBEC1 by phosphorylating its uracil-DNA glycosylase, protecting its genome in neurons. Inhibiting this pathway via AAV-UGI protects against encephalitis, suggesting a new route for antiviral intervention. Nature Microbiology: www.nature.com/articles/s41...

Cancer therapy resistance is shaped by dynamic, co-evolving genetic and non-genetic processes. ARTNet researchers propose a next-gen framework using spatial omics, lineage tracing, and functional models to anticipate and overcome resistance. Nature Reviews Cancer: www.nature.com/articles/s41...

The CHALLENGE trial demonstrates that post-chemotherapy structured exercise significantly improves survival in resected colon cancer patients—5-year DFS up by 6.4%, 8-year OS up by 7.1%. Landmark level 1 evidence for exercise as a therapeutic modality. NEJM: www.nejm.org/doi/full/10....

Skeletal muscle proteome and phosphoproteome stratify insulin sensitivity better than clinical diagnosis. Despite sex-based metabolic differences, insulin-resistant signatures are conserved. AMPKγ3 S65 phosphorylation emerges as a potential muscle-specific target. Cell: www.cell.com/cell/fulltex...

Systematic analysis of multicellular coordination across tissues shows dynamic, age- and state-dependent cell modules. In cancer, the coordination is rewired—healthy ecosystems collapse, and a universal tumor ecosystem emerges. Nature: www.nature.com/articles/s41...

Leveraging early postnatal HSPC trafficking, in vivo lentiviral gene therapy achieves durable correction in mouse models of inherited disorders. Fanconi anaemia showed near-complete reconstitution due to selective advantage of edited cells. Nature: www.nature.com/articles/s41...

Trametinib extends mouse lifespan and healthspan, and combines additively with rapamycin. The dual treatment reduced tumors, neuroinflammation, and age-related brain glucose uptake—supporting repurposing for gerotherapy. Nature Aging: www.nature.com/articles/s43...

Interrupting CAG or GAA repeats via AAV-delivered base editors reduced somatic expansion in models of HD and FRDA. The approach recapitulates naturally stable alleles and may offer a preventive strategy against TNR-driven neurodegeneration. Nature Genetics: www.nature.com/articles/s41...

In an integrated analysis of >500 patients, co-mutations (e.g. KEAP1) and low TTF1 expression were key determinants of sotorasib efficacy in KRASG12C-mutant NSCLC. ctDNA clearance during treatment may refine response prediction. Nature Medicine: www.nature.com/articles/s41...

The TuPro project shows clinical feasibility of real-time multiomics in melanoma care. In difficult-to-treat patients, omics-guided therapy achieved 38% ORR and 54% disease control, supporting its integration into routine decision-making. Nature Medicine: www.nature.com/articles/s41...

A deep learning framework, InterpolAI, enables accurate interpolation of biomedical image stacks by tracking large image motions via optical flow. Validated across diverse modalities, it restores resolution and tissue continuity for improved 3D mapping. NatureMethods www.nature.com/articles/s41...

Cryo-EM and polysome profiling reveal that poxvirus infection remodels the 40S ribosome to support translation of both viral mRNAs and selective host transcripts like JUN, via non-canonical initiation pathways. NatMicrobio: www.nature.com/articles/s41...

A bacterial defense system uses an RNA-templated reverse transcriptase to produce covalently protein-linked poly-dA upon phage attack. "Protein-primed synthesis" halts infection via abortive growth arrest, defining a new RT-driven immune strategy. Nature: www.nature.com/articles/s41...

A linker-free design enables small, drug-like PROTACs that mediate GID4-dependent degradation of ALK and BCR-ABL. Demonstrated oral bioavailability and in vivo efficacy indicate suitability for therapeutic protein degradation strategies. Nature Communications: www.nature.com/articles/s41...

Most tumor antigens in high-TMB cancers like melanoma and NSCLC are not mutation-derived but from aberrantly expressed or lineage-specific unmutated regions. Findings call for broader immunotherapy strategies beyond mutated neoantigens. Nature Cancer (open): www.nature.com/articles/s43...

A photo-crosslinking and mass spec–based workflow maps >1,000 proteins in direct contact with DNA in living cells, generating a high-resolution atlas with single-amino-acid peptide-DNA interfaces and revealing fast chromatin responses and regulatory dynamics. Cell: www.cell.com/cell/fulltex...

Targeted suppression of mitochondrial mRNA translation using peptide–morpholino chimeras allows live-cell interrogation of mitochondrial gene expression, opening new paths to study its roles in health and disease. Science: www.science.org/doi/10.1126/...

A deep learning–guided strategy enables de novo design of dynamic proteins that switch between defined conformations. Validation shows atomic precision and Ca²⁺-controlled switching, laying groundwork for programmable signaling systems. Science: www.science.org/doi/10.1126/...

A systematic review of NHANES-based studies reveals a surge in formulaic single-factor analyses, often lacking proper design, false discovery correction, or justification—highlighting how AI-ready datasets can be exploited by paper mills. PLoS Biology: journals.plos.org/plosbiology/...

"Genome-wide association study of long COVID" A GWAS meta-analysis reveals FOXP4 as a long COVID–associated locus, pointing to lung-specific genetic pathways distinct from acute COVID severity. Findings offer clues to disease mechanisms and risk stratification. NatGen: www.nature.com/articles/s41...

By limiting serotonin availability in tumors, SERT suppresses T cell–mediated antitumor activity. SSRI treatment reactivates T cells and improves PD-1 therapy efficacy, revealing a serotonin-dependent regulatory axis. Cell (open access): www.cell.com/cell/fulltex...

>1,000 enhancer AAVs and 15 transgenic mouse lines were developed for precise genetic access to cortical cell types. Tools reached >90% specificity and are publicly available, enabling systematic functional studies of cortical circuits. Cell (open): www.cell.com/cell/fulltex...

PCSK9 controls metastatic organotropism in pancreatic cancer by regulating cholesterol handling: low-PCSK9 cells colonize LDL-rich liver via mTORC1 and oxysterol signaling, while high-PCSK9 cells adapt to lung by producing ferroptosis-protective sterols. Nature: www.nature.com/articles/s41...

An in vivo screen identified 22 compounds that block P. falciparum in mosquitoes. Lead ELQs targeting CytB remained potent in insecticide-resistant vectors and can be embedded in bed nets to halt malaria transmission. Nature (Open access): www.nature.com/articles/s41...

Aging impairs CAR-T cell efficacy by depleting NAD, leading to mitochondrial dysfunction and loss of stemness. Restoring NAD via CD38 inhibition + NMN rescues antitumor activity in old CAR-T cells. Nature Cancer: www.nature.com/articles/s43...

Transient prime editing via mRNA–LNP delivery corrected the Pah-enu2 mutation in PKU mice, reducing blood phenylalanine levels below therapeutic thresholds. This approach offers a scalable, non-viral strategy for treating genetic liver diseases. NatBioEng: www.nature.com/articles/s41...

Synonymous mutations can affect transcription, splicing, translation, and organismal fitness. Their widespread functionality challenges the neutrality assumption foundational to molecular evolution and disease models.

A systemically delivered siRNA conjugate, designed to bind albumin and resist degradation, targets MMP13 in arthritic joints. In OA and RA models, a single dose achieved sustained joint retention, gene silencing, and reduced cartilage erosion over 30 days. NatBioEng: www.nature.com/articles/s41...

APOBEC3 mutagenesis fuels resistance in HR+ metastatic breast cancer. Active before and after therapy, it drives RB1 loss and other alterations. A3A/B activity emerges as a biomarker and potential therapeutic target. Nature Genetics: www.nature.com/articles/s41...

P. falciparum’s FIKK kinases—once thought to lack tyrosine activity—diversified via loop evolution to enable host remodeling. Despite substrate divergence, a conserved ATP pocket allows one compound to inhibit all, suggesting a new antimalarial strategy. Nat Microbio: www.nature.com/articles/s41...

Therapeutic cancer vaccines—personalized/off-the-shelf—targeting neoantigens show promising clinical efficacy, particularly when combined with immune modulators. Addressing ongoing challenges such as immune evasion will further unlock their full potential. NatRevCancer www.nature.com/articles/s41...