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CA-IV-directed small-molecule shuttle enables targeted brain delivery of biologics. ca - iv导向的小分子穿梭使生物制剂的靶向脑递送成为可能。
IF 15.8 1区 生物学
Nature chemical biology Pub Date : 2026-08-26 DOI: 10.1038/s41589-026-02294-y
Xiaozhe Ding, Xinhong Chen, Philip Boehm, Alba Carretero-Cerdán, Seongmin Jang, Erin E Sullivan, Cynthia M Arokiaraj, Fiona Ristic, Bill C Kavvathas, Lillian J Campos, Jitendra Sharma, Shawn Kamboj, Yaping Lei, Mona Shahgholi, Danielle Mantin, Andrew S Fox, Timothy F Shay, Sarah E Reisman, Viviana Gradinaru
{"title":"CA-IV-directed small-molecule shuttle enables targeted brain delivery of biologics.","authors":"Xiaozhe Ding, Xinhong Chen, Philip Boehm, Alba Carretero-Cerdán, Seongmin Jang, Erin E Sullivan, Cynthia M Arokiaraj, Fiona Ristic, Bill C Kavvathas, Lillian J Campos, Jitendra Sharma, Shawn Kamboj, Yaping Lei, Mona Shahgholi, Danielle Mantin, Andrew S Fox, Timothy F Shay, Sarah E Reisman, Viviana Gradinaru","doi":"10.1038/s41589-026-02294-y","DOIUrl":"10.1038/s41589-026-02294-y","url":null,"abstract":"<p><p>The blood-brain barrier (BBB) presents a challenge for central nervous system (CNS) therapies. Receptor-mediated transcytosis offers a solution, but existing receptor targets are ubiquitous across CNS and peripheral tissues, causing unintended exposure. We identified carbonic anhydrase IV (CA-IV) as a brain-enriched receptor enabling engineered viral capsids to cross the BBB. However, it is unclear whether CA-IV can also mediate non-viral delivery. We thus designed a reactive small-molecule shuttle, derived from an FDA-approved binder, that couples to proteins and oligonucleotides in a single step. We validated the binding of conjugated molecules to multiple mammalian CA-IV orthologs and subsequent internalization in cell-based assays. After systemic dosing, CA-IV-targeted antibody conjugates crossed the BBB in mice and neonatal macaques, preferentially accumulating in the brain and sustaining parenchymal levels for at least 7 days. This BrainCAB (Brain access through Carbonic Anhydrase-binder Bioconjugation) technology offers a compact, modular shuttle for selective and prolonged CNS delivery of large molecules.</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148830628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Entering the agentic era of AI in drug discovery 进入人工智能药物发现的代理时代。
IF 15.8 1区 生物学
Nature chemical biology Pub Date : 2026-08-19 DOI: 10.1038/s41589-026-02295-x
R. S. K. Vijayan, Jason B. Cross, Vasanthanathan Poongavanam
{"title":"Entering the agentic era of AI in drug discovery","authors":"R. S. K. Vijayan,&nbsp;Jason B. Cross,&nbsp;Vasanthanathan Poongavanam","doi":"10.1038/s41589-026-02295-x","DOIUrl":"10.1038/s41589-026-02295-x","url":null,"abstract":"Agentic AI systems are reshaping drug discovery, and the convergence of agentic AI with laboratory automation is enabling the design of self-driving laboratories that transform the design–make–test–analyze cycle into a closed-loop, adaptive workflow. Here, we discuss these advances and the potential that agentic AI holds for drug discovery.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 11","pages":"1705-1707"},"PeriodicalIF":15.8,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A chemigenetic endogenous Ras activity biosensor for live-cell pharmacology 用于活细胞药理学的化学内源性Ras活性生物传感器
IF 15.8 1区 生物学
Nature chemical biology Pub Date : 2026-08-19 DOI: 10.1038/s41589-026-02276-0
Ryan Weeks, Daojia R. Zhou, Michelle S. Frei, Jin Zhang
{"title":"A chemigenetic endogenous Ras activity biosensor for live-cell pharmacology","authors":"Ryan Weeks,&nbsp;Daojia R. Zhou,&nbsp;Michelle S. Frei,&nbsp;Jin Zhang","doi":"10.1038/s41589-026-02276-0","DOIUrl":"10.1038/s41589-026-02276-0","url":null,"abstract":"Ras is a small GTPase that regulates cell growth and proliferation. Hyperactive Ras is prevalent in cancer and has been a therapeutic target for decades. Many lines of evidence have demonstrated that Ras signals from the plasma membrane as well as noncanonical compartments such as the Golgi, making live-cell biosensors for tracking the spatiotemporal dynamics of Ras activity a valuable approach for Ras studies. However, current biosensors are limited in their quantitative capacity for measuring endogenous Ras activity. Here we introduce a chemigenetic biosensor design, making use of circularly permuted HaloTag labeled with the fluorophore JF635, for detecting endogenous Ras activity. This HaloTag-based Ras Activity Reporter (HaloRasAR) revealed the spatiotemporal dynamics of Ras activity downstream of either growth factor signaling or protein kinase C activation. In addition, live-cell characterization of a Ras(G12C) inhibitor and a Ras GEF inhibitor revealed subcellular-specific inhibition profiles. HaloRasAR represents a major advance in spatiotemporal interrogation of Ras signaling and live-cell pharmacology. Here the authors present a biosensor for measuring endogenous Ras in live cells, based on HaloTag and the fluorogenic JF635 dye, and they use it to report location-specific inhibition profiles of distinct Ras pathway drugs.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 10","pages":"1685-1692"},"PeriodicalIF":15.8,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Nature’s glues 大自然的胶水。
IF 15.8 1区 生物学
Nature chemical biology Pub Date : 2026-08-18 DOI: 10.1038/s41589-026-02310-1
Yiyun Song
{"title":"Nature’s glues","authors":"Yiyun Song","doi":"10.1038/s41589-026-02310-1","DOIUrl":"10.1038/s41589-026-02310-1","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 9","pages":"1363-1363"},"PeriodicalIF":15.8,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Gluing without a loop 没有打环的胶水。
IF 15.8 1区 生物学
Nature chemical biology Pub Date : 2026-08-18 DOI: 10.1038/s41589-026-02308-9
Grant Miura
{"title":"Gluing without a loop","authors":"Grant Miura","doi":"10.1038/s41589-026-02308-9","DOIUrl":"10.1038/s41589-026-02308-9","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 9","pages":"1363-1363"},"PeriodicalIF":15.8,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mining metal coordination 采矿金属配位。
IF 15.8 1区 生物学
Nature chemical biology Pub Date : 2026-08-18 DOI: 10.1038/s41589-026-02309-8
Huijuan Guo
{"title":"Mining metal coordination","authors":"Huijuan Guo","doi":"10.1038/s41589-026-02309-8","DOIUrl":"10.1038/s41589-026-02309-8","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 9","pages":"1363-1363"},"PeriodicalIF":15.8,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Living circuit boards built by printing bacterial transistors 印制细菌晶体管制成的活电路板
IF 14.8 1区 生物学
Nature chemical biology Pub Date : 2026-08-17 DOI: 10.1038/s41589-026-02300-3
Hamid Doosthosseini, Haorong Chen, Christopher A. Voigt
{"title":"Living circuit boards built by printing bacterial transistors","authors":"Hamid Doosthosseini, Haorong Chen, Christopher A. Voigt","doi":"10.1038/s41589-026-02300-3","DOIUrl":"https://doi.org/10.1038/s41589-026-02300-3","url":null,"abstract":"The multicellular forms and functions seen in biology are controlled by cellular communication and collective computation. Reprogramming natural systems is difficult because they comprise many signaling molecules connecting a web of regulatory networks within cells. Here we apply principles from pass transistor logic (PTL) to design bacteria that can be easily reconfigured to perform computations on a solid surface. Strains of Pantoea agglomerans were built to encode two transistors (N-type and P-type) whose inputs and outputs are small molecules. They are connected by three relay strains that convert molecular diffusion to unidirectional flow. To build circuits, an acoustic liquid handler prints patterns of these five strains on a surface. By changing the pattern, not requiring any genetic changes, different operations are implemented, including multi-input multioutput logic, demultiplexor, half-adder and full-adder. This work demonstrates that only five cell types, each encoding a simple operation, can be scaled to create complex computational operations.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"6 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Photoproximity labeling of c-Myc reveals SLK as a cancer-specific co-regulator c-Myc的光邻近标记显示SLK是癌症特异性的共同调节剂
IF 14.8 1区 生物学
Nature chemical biology Pub Date : 2026-08-13 DOI: 10.1038/s41589-026-02284-0
Ryan R. Milione, Feifei Tong, Kelsey L. Wolfe, Cameron J. Douglas, Sara B. Linker, Xinmeng Jasmine Mu, James V. Oakley, Andrew R. Nager, Michalina Janiszewska, Ciaran P. Seath
{"title":"Photoproximity labeling of c-Myc reveals SLK as a cancer-specific co-regulator","authors":"Ryan R. Milione, Feifei Tong, Kelsey L. Wolfe, Cameron J. Douglas, Sara B. Linker, Xinmeng Jasmine Mu, James V. Oakley, Andrew R. Nager, Michalina Janiszewska, Ciaran P. Seath","doi":"10.1038/s41589-026-02284-0","DOIUrl":"https://doi.org/10.1038/s41589-026-02284-0","url":null,"abstract":"Transcription factors (TFs) are aspirational therapeutic targets, as their dysregulation drives altered cell states. Yet many disease-relevant TFs are disordered and lack canonical binding pockets, frustrating direct small-molecule inhibition. Indirectly targeting the effector molecules that modulate TF function is a promising, underexplored alternative. Here we report a strategy for capturing cancer-specific protein–protein interactions using context-dependent µMap photoproximity labeling. With an intein-based method for catalyst conjugation in biochemically intact nuclei, we capture unique c-Myc interactomes in healthy and cancerous prostate cells and mine them for druggable vulnerabilities. We identify STE20-like kinase (SLK), a cancer-specific interactor that stabilizes c-Myc, drives epithelial morphology and is essential for tumorigenesis. Mechanistically, SLK phosphorylates c-Myc at serine 329, antagonizing GSK3β-dependent phosphodegron phosphorylation. This interaction is associated with a splicing change promoting nuclear localization of the long SLK isoform. Patient data link this isoform to c-Myc target expression across tumor types; the interaction validates across diverse tissues.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"67 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A dual assault on KRAS. 对KRAS的双重攻击。
IF 15.8 1区 生物学
Nature chemical biology Pub Date : 2026-08-12 DOI: 10.1038/s41589-026-02283-1
Dasom Kim, Junhyung Isaac Lee, Dongsung Kim
{"title":"A dual assault on KRAS.","authors":"Dasom Kim, Junhyung Isaac Lee, Dongsung Kim","doi":"10.1038/s41589-026-02283-1","DOIUrl":"10.1038/s41589-026-02283-1","url":null,"abstract":"","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148722714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Brønsted-basic small molecules activate GTP hydrolysis in KRAS-Q61 mutants. br ønsted-碱性小分子激活KRAS-Q61突变体的GTP水解。
IF 15.8 1区 生物学
Nature chemical biology Pub Date : 2026-08-12 DOI: 10.1038/s41589-026-02291-1
Ye-Cheng Wang, Si-Cong Chen, Yang Cao, Yang Wu, Zhongda Shi, Celine D Wang, Michael A Norinskiy, Hasan Celik, Ziyang Zhang
{"title":"Brønsted-basic small molecules activate GTP hydrolysis in KRAS-Q61 mutants.","authors":"Ye-Cheng Wang, Si-Cong Chen, Yang Cao, Yang Wu, Zhongda Shi, Celine D Wang, Michael A Norinskiy, Hasan Celik, Ziyang Zhang","doi":"10.1038/s41589-026-02291-1","DOIUrl":"10.1038/s41589-026-02291-1","url":null,"abstract":"<p><p>The RAS family of oncogenes (KRAS, HRAS, NRAS) is among the most frequently mutated genes in human cancer. Therapeutic development has largely focused on inhibitors for KRAS codon 12 mutations, while mutant-selective inhibitors for Q61 variants remain elusive. A common mechanistic feature of G12 and Q61 mutants is the reduced efficiency of GTP hydrolysis, which enriches RAS in its active, signaling-competent state. Here we report small molecules that accelerate GTP hydrolysis in KRAS-Q61 mutants as an alternative therapeutic strategy. These compounds compensate for the loss of the catalytic residue Gln61 by introducing a general base into the active site, selectively enhancing hydrolysis of KRAS-Q61X (X = H, L, K, R) mutants by up to 20-fold. In mutant cancer cell lines, these compounds reduce GTP-bound RAS levels and suppress downstream signaling. This work establishes a mechanistic foundation for small-molecule 'GTPase activators' and offers a new paradigm for targeting RAS-driven cancers.</p>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148725375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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