ACS Bio & Med Chem Au最新文献_第4页

Epidermal Growth Factor Receptor as a Model Drug Target for Scrutinizing the Status Quo in Drug Discovery and Chemical Biology 表皮生长因子受体作为模型药物靶点审视药物发现和化学生物学的现状

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-08-19 Epub Date: 2026-06-17 DOI: 10.1021/acsbiomedchemau.6c00089

David E. Heppner, Monica R. MacDonald, Nader N. Nasief, Shilpa E. Naik, Sahba Cunningham

引用次数: 0

A Picomolar MBP-Binding Nanobody for Target Enrichment and Modular Complex Engineering 一种用于目标富集和模块化复杂工程的皮摩尔mbp结合纳米体

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-08-19 Epub Date: 2026-07-06 DOI: 10.1021/acsbiomedchemau.6c00053

Monica Chinellato, Elisa Franzin, Filippo Vascon, Paul-Albert Koenig, Florian I. Schmidt, Patrizia Pontisso, Laura Cendron

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Dimethylindanoylindole Isomers Revealed Different Pharmacological Profiles at CB1 and CB2 Cannabinoid Receptors 二甲基林丹酰吲哚异构体在CB1和CB2大麻素受体上显示不同的药理特征

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-08-19 Epub Date: 2026-07-01 DOI: 10.1021/acsbiomedchemau.6c00090

Soo Jung Oh, Ruiru Guo, Christopher Lucaj, Neshira Gutierrez, Kh Tanvir Ahmed, Alexander H. Williams, Chang-Guo Zhan, Gregory B. Dudley, Hideaki Yano

{"title":"Dimethylindanoylindole Isomers Revealed Different Pharmacological Profiles at CB1 and CB2 Cannabinoid Receptors","authors":"Soo Jung Oh, Ruiru Guo, Christopher Lucaj, Neshira Gutierrez, Kh Tanvir Ahmed, Alexander H. Williams, Chang-Guo Zhan, Gregory B. Dudley, Hideaki Yano","doi":"10.1021/acsbiomedchemau.6c00090","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00090","url":null,"abstract":"Synthetic cannabinoid receptor agonists (SCRAs) exhibithigherefficacy and potency at CB1 and CB2 cannabinoid receptors comparedto Δ9-tetrahydrocannabinol, contributing to adverseeffects associated with their growing prevalence as novel psychoactivesubstances. The indole-based SCRAs GBD-002 and GBD-003, incorporating2,2-dimethylindane, differ by a single substituent position yet displaymarkedly different receptor binding profiles. We evaluated both theGBD-002/GBD-003 pair and an analogous structural isomer pair JWH-018/JWH-0182′-naphthyl using bioluminescence resonance energy transfer(BRET) assays to assess key CB1 and CB2 transducer pathways, includingGαi1 engagement, β-arrestin 2 recruitment,and cAMP inhibition. Site-directed mutagenesis characterized contributionsof nonconserved residues between CB1 and CB2 as well as aromatic residueson CB1 transmembrane helix 2 (TM2). This study provided insights intothe molecular determinants of cannabinoid receptor selectivity andefficacy.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 4","pages":"432–442"},"PeriodicalIF":3.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An Isogenic Yeast Model Reveals the Influence of Native Promoter G-Quadruplex Forming Sequences on P53 and NF-κB Transactivation 等基因酵母模型揭示天然启动子g -四重体形成序列对P53和NF-κB转激活的影响

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-08-19 Epub Date: 2026-07-04 DOI: 10.1021/acsbiomedchemau.6c00109

Libuše Kratochvilová, Petr Orság, Karolína Drápalová, Radim Stříž, Zeinab El Rashed, Paola Menichini, Rieko Ohki, Paola Monti, Alberto Inga, Václav Brázda

{"title":"An Isogenic Yeast Model Reveals the Influence of Native Promoter G-Quadruplex Forming Sequences on P53 and NF-κB Transactivation","authors":"Libuše Kratochvilová, Petr Orság, Karolína Drápalová, Radim Stříž, Zeinab El Rashed, Paola Menichini, Rieko Ohki, Paola Monti, Alberto Inga, Václav Brázda","doi":"10.1021/acsbiomedchemau.6c00109","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00109","url":null,"abstract":"G-quadruplexes (G4s)are noncanonical, four-strandednucleic acidstructures formed in guanine-rich regions that influence many biologicalprocesses, including transcription. We previously developed a yeast-basedsystem to study the transcriptional modulation of p53 family proteinsby G4-forming sequences (G4FS) using artificial constructs. Here,motivated by the observation of genome-wide enrichment of G4FS inproximity to p53 and NF-κB response elements (REs), we examinedhow native combinations of G4FS and REs derived from human promotersinfluence the activity of p53 or NF-κB family proteins. To thisend, five pairs of isogenic reporter strains were developed, and thepropensity of G4FS to adopt G4 structures was confirmed by in vitro assays. Results in yeast showed that the presenceof G4FS enhanced the transcriptional output of partial-function p53mutants, p63, and p73 relative to wild-type p53, suggesting a generalboost in the activity of weaker transcription factor proteins. Conversely,the effect of G4FS on transactivation by NF-κB proteins wascontext-dependent and mainly inhibitory. In conclusion, our findingshighlight the importance of DNA topology in transcriptional regulationby both p53 and NF-κB proteins and demonstrate that the yeast-basedsystem serves as a valuable tool for isolating the contribution ofG4FS within a controlled genomic context.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 4","pages":"456–467"},"PeriodicalIF":3.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Physicochemical and Metabolic Optimization of NAMPT Inhibitors Enables Effective Antibody–Drug Conjugates for Liquid and Solid Tumors NAMPT抑制剂的物理化学和代谢优化使液体和实体肿瘤有效的抗体-药物偶联物

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-08-19 Epub Date: 2026-07-13 DOI: 10.1021/acsbiomedchemau.6c00047

Pablo Ruedas, Hendrik Gruss, Alexander Hempelmann, Marija Vranic, Sarah-Jane Neuberth, Valentin Petrich, Dominic Gross, Anikó Pálfi, Andreas M Pahl, Torsten Hechler

{"title":"Physicochemical and Metabolic Optimization of NAMPT Inhibitors Enables Effective Antibody–Drug Conjugates for Liquid and Solid Tumors","authors":"Pablo Ruedas, Hendrik Gruss, Alexander Hempelmann, Marija Vranic, Sarah-Jane Neuberth, Valentin Petrich, Dominic Gross, Anikó Pálfi, Andreas M Pahl, Torsten Hechler","doi":"10.1021/acsbiomedchemau.6c00047","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00047","url":null,"abstract":"Antibody drug conjugates(ADCs) enable selective deliveryof highlypotent small molecules, yet most clinically validated payloads targetsolely cell-division pathways with several drawbacks such as highoff-target toxicity and a lack of efficacy on nondividing tumor cells(e.g., tumor stem cells). Metabolic targets such as nicotinamide phosphoribosyltransferase(NAMPT) offer a complementary mode of action and are predestined asADC payloads since systemic toxicities have prevented clinical useof NAMPT inhibitors (NAMPTi) as free drugs. Here we show that highlyhydrophobic NAMPTi, especially cyanoguanidine-containing inhibitors,are chemically and metabolically suboptimal for ADC deployment dueto limited efficacy likely due to lysosomal conversion to inactiveguanylureas. Guided by structure-based design, and molecular dynamicssimulations, we developed two next-generation NAMPT inhibitors featuring(i) a tertiary alcohol to balance hydrophilicity and (ii) an isoindoline-ureagroup to improve lysosomal stability in comparison to the cyanoguanidine.The optimized inhibitors retained high affinity to the NAMPT enzymeand showed strong cellular activity upon targeted delivery throughADCs. When conjugated to anti-CD30, anti-HER2, or anti-TROP2 antibodies,the resulting ADCs showed durable responses in hematologic and solidtumor models, including complete regressions in the metabolicallystringent NCI-N87 gastric carcinoma xenograft after a single 2 mg/kgdose. These findings highlight physicochemical tuning and lysosomalstability as key design principles for NAMPT-based payloads and supportNAMPT inhibition as a very promising mode of action (MoA) for next-generationADC therapeutics.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 4","pages":"353–367"},"PeriodicalIF":3.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Advancements in Technologies Targeting Horizontal Gene Transfer─Routes to Control Drug Resistance Evolution 靶向水平基因转移技术的进展控制耐药性进化的途径。

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-06-17 Epub Date: 2026-04-09 DOI: 10.1021/acsbiomedchemau.5c00273

Samuel Chetachukwu Adegoke, Md Adnan Karim, Maurelio Cabo Jr, Ignatius Senyo Yao Yawlui, Dennis LaJeunesse

{"title":"Advancements in Technologies Targeting Horizontal Gene Transfer─Routes to Control Drug Resistance Evolution","authors":"Samuel Chetachukwu Adegoke, Md Adnan Karim, Maurelio Cabo Jr, Ignatius Senyo Yao Yawlui, Dennis LaJeunesse","doi":"10.1021/acsbiomedchemau.5c00273","DOIUrl":"10.1021/acsbiomedchemau.5c00273","url":null,"abstract":"The global rise ofmultidrug-resistant (MDR) bacteriaposes a majorpublic health crisis, threatening the effectiveness of modern medicine.Traditional antibiotic development struggles to keep pace with bacterialevolution, largely due to the rapid dissemination of antibiotic resistancegenes via horizontal gene transfer (HGT). HGT mechanisms both canonicaland noncanonical enable bacteria to acquire resistance traits definingspecies and even special challenges. In this review, we cover thecurrent understanding of HGT in spreading antibiotic resistance andexplore possible strategies to control HGT and slow the spread ofantimicrobial resistance. Recent advances highlight the potentialof synthetic competence inhibitors, advanced oxidation processes (AOPs),CRISPR-Cas technologies, gene drives, and antiplasmids to disrupthorizontal gene flow and mitigate resistance evolution. Despite promisinglaboratory results, challenges remain in translating these approachesinto clinical and environmental applications. Blocking HGT could complementantimicrobial stewardship programs and traditional antibiotic therapiesby curbing the emergence of new resistant strains at their geneticroots. By targeting the foundational mechanisms of resistance acquisition,these strategies offer a proactive pathway to extend the efficacyof existing antibiotics and prevent a “postantibiotic”era. Ongoing research into bacterial pathogenesis, genome defensesystems, and innovative gene-editing technologies will be criticalto developing effective, scalable solutions for managing MDR infectionsworldwide.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 3","pages":"210–236"},"PeriodicalIF":3.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148296741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Carborane Hydrophobic Tags Drive Selective Degradation of Endogenous KRASG12C via HSP70–Ubiquitin–Proteasome Pathway 碳硼烷疏水标签通过hsp70 -泛素-蛋白酶体途径驱动内源性KRASG12C的选择性降解。

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-06-17 Epub Date: 2026-03-10 DOI: 10.1021/acsbiomedchemau.6c00004

Yujie Shao, Kazuki Miura, Hiroyuki Nakamura

{"title":"Carborane Hydrophobic Tags Drive Selective Degradation of Endogenous KRASG12C via HSP70–Ubiquitin–Proteasome Pathway","authors":"Yujie Shao, Kazuki Miura, Hiroyuki Nakamura","doi":"10.1021/acsbiomedchemau.6c00004","DOIUrl":"10.1021/acsbiomedchemau.6c00004","url":null,"abstract":"Persistent activation of the Kirsten rat sarcoma viraloncogenehomologue (KRAS)G12C mutation sustains oncogenic signaling,and covalent inhibitors often yield incomplete pathway suppressionor resistance. Herein, we developed hydrophobic-tag (HyT) degradersby introducing a carborane cluster into MRTX849, an KRASG12C covalent ligand, to promote selective elimination of endogenousKRASG12C. The carborane-HyT conjugates (HY8) reduced KRASG12C abundance and ERK phosphorylation inmutant cancer cells while showing lower intrinsic cytotoxicity andactivity equal or superior to the adamantane-HyT analogue (HY5). Mechanistic studies indicate that HY8 acts in anE3 ligase-independent, chaperone-assisted pathway. KRAS degradationwas rescued by the proteasome inhibitor MG132, but not by the lysosomalinhibitor bafilomycin A1, consistent with the increased level of KRASubiquitination and heat shock protein 70 engagement. Competition withMRTX849 blocked KRAS degradation, supporting on-target covalent engagementat Cys12. These findings establish carborane as a compact, functionalHyT that drives proteasome-dependent degradation of endogenous KRASG12C and suppresses downstream signaling, broadening degraderdesign to include an E3-independent modality for the degradation ofoncogenic proteins.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 3","pages":"272–281"},"PeriodicalIF":3.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148296731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Combining Topography and Chemistry toward Polydopamine Antibacterial Surfaces 结合地形学和化学研究聚多巴胺抗菌表面。

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-06-17 Epub Date: 2026-04-19 DOI: 10.1021/acsbiomedchemau.5c00242

Leonardo Moscolari, Simona Tomaselli, Francesco Galeotti, Erika Kozma

{"title":"Combining Topography and Chemistry toward Polydopamine Antibacterial Surfaces","authors":"Leonardo Moscolari, Simona Tomaselli, Francesco Galeotti, Erika Kozma","doi":"10.1021/acsbiomedchemau.5c00242","DOIUrl":"10.1021/acsbiomedchemau.5c00242","url":null,"abstract":"Microporous antibacterial surfaces offer a promisingroute forpreventing bacterial adhesion and biofilm formation, yet their fabricationoften involves complex and energy consuming processes. In this work,we present a sustainable strategy for producing multifunctional antibacterialsurfaces by combining a microporous cellulose acetate butyrate (CAB)substrate, a bioinspired polydopamine (PDA) coating, and in situ synthesizedsilver nanoparticles (AgNPs). CAB, selected for its film-forming capabilityand ease of microstructuring via spin-coating, provides a tunableplatform for topographical control. PDA, formed through the oxidativeself-polymerization of dopamine, serves as a conformal adhesive layerand simultaneously acts as a reductive matrix for AgNP formation.Immersion in silver nitrate solution enables the direct depositionof AgNPs without external reducing agents, facilitated by the catecholfunctionalities of PDA. The resulting CAB–PDA–AgNP surfacesexhibit enhanced antibacterial activity through the combined effectsof patterning, surface chemistry, and silver-mediated bactericidalaction. The fabrication process is low-energy and solvent-minimized,aligning with principles of sustainable material development and offeringa versatile platform for antibacterial coatings.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 3","pages":"254–262"},"PeriodicalIF":3.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148296749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proton Transfer Mechanisms in the MmpL3 Transporter of Mycobacterium tuberculosis Studied by Computer Simulations 结核分枝杆菌MmpL3转运体中质子转移机制的计算机模拟研究

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-06-17 Epub Date: 2026-03-27 DOI: 10.1021/acsbiomedchemau.5c00274

Yong-Sok Lee, Sergio A. Hassan, Darrell E. Hurt

{"title":"Proton Transfer Mechanisms in the MmpL3 Transporter of Mycobacterium tuberculosis Studied by Computer Simulations","authors":"Yong-Sok Lee, Sergio A. Hassan, Darrell E. Hurt","doi":"10.1021/acsbiomedchemau.5c00274","DOIUrl":"10.1021/acsbiomedchemau.5c00274","url":null,"abstract":"The mycobacterial membrane exporter MmpL3 transportstrehalosemonomycolates (TMM) from the cytosol to the outer membrane of Mycobacterium tuberculosis, making it a potentialdrug target. Proton influx is believed to drive TMM efflux, suggestingthat disrupting proton transfer (PT) could be therapeutic. However,the PT mechanism and its relation to function remain unclear. RecentMmpL3 structures reveal a potential proton channel in its hydrophobiccore, which also binds potential antituberculosis compounds. We investigatedthe PT process using hybrid quantum-mechanical/molecular-mechanicaland classical molecular dynamics simulations. We show that transientwater chains form in two connected transmembrane cavities that actas proton conduits. Four consecutive PT events are necessary to alterthe protonation states of acidic residues in the protein core, triggeringconformational changes that affect the TMM binding site. The processbegins with the tandem movement of two protons through an upper cavity,protonating two aspartate residues via a classical hydronium migration.After conformational shifts, PT proceeds through a lower cavity, protonatingtwo glutamate residues near the cytosolic opening and inducing furtherconformational shifts; here, PT occurs sequentially via hydroniumand proton-hole migration. The cycle ends with the release of protonsinto the cytosol. Based on the observed conformational changes, wepropose a mechanism for TMM efflux.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 3","pages":"263–271"},"PeriodicalIF":3.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148296736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Encapsulation of Exosomal Volatile Organic Compounds for Modulating the NF-κB Pathway in Monocytes 外泌体挥发性有机化合物包封对单核细胞NF-κB通路的调节作用。

IF 3.5

ACS Bio & Med Chem Au Pub Date : 2026-06-17 Epub Date: 2026-03-16 DOI: 10.1021/acsbiomedchemau.5c00241

Dina Hashoul, Rand Shibel, Haya Dahamshy-Silawi, Elias Mansour, Nisrine Lahoud Jeries, Walaa Saliba, Yoav Broza, Assaf C. Bester, Hossam Haick

引用次数: 0