Journal of Enzyme Inhibition and Medicinal Chemistry最新文献

Synthetic strategies and therapeutic insights into FDA-approved indole-containing drugs. fda批准的含吲哚药物的合成策略和治疗见解。

IF 5.4 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2026-12-01 Epub Date: 2026-01-27 DOI: 10.1080/14756366.2026.2616556

Tengjiao Yang, Yanfeng Zhang, Peng Liu, Peng Qi, Xiankai Li, Wubin Zhi, Lijie Zhao

{"title":"Synthetic strategies and therapeutic insights into FDA-approved indole-containing drugs.","authors":"Tengjiao Yang, Yanfeng Zhang, Peng Liu, Peng Qi, Xiankai Li, Wubin Zhi, Lijie Zhao","doi":"10.1080/14756366.2026.2616556","DOIUrl":"10.1080/14756366.2026.2616556","url":null,"abstract":"Indole is a privileged heteroaromatic scaffold in medicinal chemistry, characterised by its unique physicochemical properties, hydrogen-bonding potential, and bioisosteric versatility. Over the past decades, numerous indole-containing drugs have been approved by the Food and Drug Administration (FDA), spanning diverse therapeutic areas including oncology, infectious diseases, gastrointestinal disorders, neurological conditions, and cardiovascular diseases. This review provides a comprehensive survey of FDA-approved indole-based drugs, with particular emphasis on those approved from 2013 to the present. Representative synthetic strategies are highlighted to illustrate the versatility of the indole framework in drug design. Furthermore, we systematically discuss each drug's pharmacology, mechanisms of action, and clinical applications. By integrating synthetic chemistry with clinical applications, this review aims to provide medicinal chemists and drug developers with guidance for leveraging indole scaffolds in next-generation therapeutic discovery and development.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"41 1","pages":"2616556"},"PeriodicalIF":5.4,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12854230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146064180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Diethyl Phthalate (DEP) as a potential osteosarcoma risk factor: a multi-omics study integrating network Toxicology, single-cell RNA sequencing, and molecular docking. 邻苯二甲酸二乙酯（DEP）作为潜在的骨肉瘤危险因素：一项整合网络毒理学、单细胞RNA测序和分子对接的多组学研究

IF 5.4 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2026-12-01 Epub Date: 2026-02-16 DOI: 10.1080/14756366.2025.2611582

Shangqi Yin, Wuzheng Liu, Chunxiao Gao, Chunyan Li, Jun Wu

{"title":"Diethyl Phthalate (DEP) as a potential osteosarcoma risk factor: a multi-omics study integrating network Toxicology, single-cell RNA sequencing, and molecular docking.","authors":"Shangqi Yin, Wuzheng Liu, Chunxiao Gao, Chunyan Li, Jun Wu","doi":"10.1080/14756366.2025.2611582","DOIUrl":"10.1080/14756366.2025.2611582","url":null,"abstract":"Diethyl phthalate (DEP), a common plasticiser and endocrine disruptor, has been linked to cancer, but its role in osteosarcoma (OS) remains unclear. This study integrated network toxicology, transcriptomics, protein-protein interaction (PPI) analysis, machine learning, molecular docking, molecular dynamics (MD), single-cell RNA sequencing (scRNA-seq), and external validation to investigate DEP-related mechanisms in OS. We identified 45 DEP-responsive genes enriched in extracellular matrix-related pathways. PPI network analysis revealed 11 hub genes, of which LASSO, SVM-RFE, and Boruta algorithms consistently prioritised P4HA2, COL18A1, and COL10A1. Docking and MD simulations supported stable binding of DEP to P4HA2 and COL18A1 via hydrogen bonds and hydrophobic interactions. scRNA-seq demonstrated celltype-specific expression of these genes. Validation cohorts confirmed their upregulation in OS, with AUC values up to 0.950. These findings suggest that DEP may promote OS progression by targeting extracellular matrix remodelling, offering new diagnostic biomarkers and hypothesis-generating evidence for environmental osteocarcinogenesis.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"41 1","pages":"2611582"},"PeriodicalIF":5.4,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12912210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146201859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cynanchum wilfordii modulates inflammatory responses in LPS-stimulated RAW264.7 cells via the NF-κB and MAPK pathways. 雷公藤通过NF-κB和MAPK通路调节lps刺激的RAW264.7细胞的炎症反应。

IF 5.4 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2026-12-01 Epub Date: 2026-01-22 DOI: 10.1080/14756366.2025.2568085

Yun-Jeong Ji, Min Hye Kang, Sin Hee Han, Young-Seob Lee, Myoung-Jin Kim, Jang Hoon Kim, Gwi Yeong Jang

{"title":"Cynanchum wilfordii modulates inflammatory responses in LPS-stimulated RAW264.7 cells via the NF-κB and MAPK pathways.","authors":"Yun-Jeong Ji, Min Hye Kang, Sin Hee Han, Young-Seob Lee, Myoung-Jin Kim, Jang Hoon Kim, Gwi Yeong Jang","doi":"10.1080/14756366.2025.2568085","DOIUrl":"10.1080/14756366.2025.2568085","url":null,"abstract":"Cynanchum wilfordii is a widely used herb in Oriental medicine, known for its wide range of therapeutic applications. The present study was conducted with the aim of evaluating the effects of selected compounds isolated from C. wilfordii, including 4-hydroxyacetophenone (CW1), 2,4-dihydroxyacetophenone (CW2), wilfoside K1N (CW3), and cynandione A (CW4), on the inflammatory response induced by treatment of macrophages with LPS. The study focused on the analysis of the MAPK and NF-κB pathways. The results showed that treatment with CW1, CW2, CW3 and CW4 inhibited the expression of p-ERK, p-JNK, p-p38 and p-IkBa in LPS-induced macrophages, with CW4 exhibiting the greatest inhibitory effects. Furthermore, CW4 treatment showed the most significant inhibitory effect on p-IκB-α/IκB-α expression in the NF-κB pathway. In conclusion, the data demonstrate that CW4 exerts a robust inhibitory effect on macrophage inflammatory signalling pathways in the LPS-induced inflammatory response.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"41 1","pages":"2568085"},"PeriodicalIF":5.4,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12829426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146018894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Integrating virtual screening and molecular dynamics simulations to identify emodin as a PYCR1 inhibitor modulating docetaxel sensitivity in prostate cancer. 结合虚拟筛选和分子动力学模拟鉴定大黄素作为PYCR1抑制剂调节前列腺癌中多西他赛的敏感性。

IF 5.4 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2026-12-01 Epub Date: 2026-02-10 DOI: 10.1080/14756366.2026.2622725

Shuai Liu, Yongfeng Lao, Long Cheng, Xi Xiao, Longtu Ma, Wenyun Wang, Kun Zhao, Wenxuan Li, Zhongze Zhou, Qingchao Li, Yan Tao, Shanhui Liu, Zhilong Dong

{"title":"Integrating virtual screening and molecular dynamics simulations to identify emodin as a PYCR1 inhibitor modulating docetaxel sensitivity in prostate cancer.","authors":"Shuai Liu, Yongfeng Lao, Long Cheng, Xi Xiao, Longtu Ma, Wenyun Wang, Kun Zhao, Wenxuan Li, Zhongze Zhou, Qingchao Li, Yan Tao, Shanhui Liu, Zhilong Dong","doi":"10.1080/14756366.2026.2622725","DOIUrl":"10.1080/14756366.2026.2622725","url":null,"abstract":"Docetaxel (DTX) resistance is the main cause of treatment failure in castration-resistant prostate cancer (CRPC). Pyrroline-5-carboxylic acid reductase 1 (PYCR1) is an enzyme involved in proline metabolism. It is highly expressed in various cancers and promotes malignant progression, yet its role in DTX resistance in prostate cancer remains unclear. In this study, bioinformatics analyses and in vitro/vivo experiments demonstrated that interfering with PYCR1 expression modulates the sensitivity of prostate cancer cells to DTX. Subsequently, via structure-based virtual screening, molecular dynamics simulations, and cellular thermal shift assay (CETSA), emodin-an anthraquinone compound-was identified as a PYCR1-targeting agent. Collectively, these findings suggest that PYCR1 may serve as a key target mediating DTX resistance in prostate cancer, and the emodin-DTX combination provides a promising potential clinical strategy to overcome such resistance. Finally, its functions and safety were also verified through in vitro experiments.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"41 1","pages":"2622725"},"PeriodicalIF":5.4,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12893152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of the first peptide inhibitor of UBE2C enzymatic activity: insights from metadynamics-guided folding and binding studies. 第一个UBE2C酶活性肽抑制剂的鉴定：来自元动力学指导的折叠和结合研究的见解。

IF 5.4 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2026-12-01 Epub Date: 2026-01-06 DOI: 10.1080/14756366.2025.2605383

Luciano Pirone, Bianca Fiorillo, Annarita Del Gatto, Rita Russo, Alessandra Guarracino, Chiara Cassiano, Laura Zaccaro, Federica Moraca, Emilia Pedone, Bruno Catalanotti

引用次数: 0

Over-expression, purification, and kinetic analysis of Mycobacterium tuberculosis WecA. 结核分枝杆菌WecA的过表达、纯化及动力学分析。

IF 5.4 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2026-12-01 Epub Date: 2026-01-08 DOI: 10.1080/14756366.2025.2610028

Yishu Zhao, Haiying Jia, Yan Wang, Shanshan Sha, Dong An, Shufeng Yang, Lei Qian, Yufang Ma, Liming Xu

{"title":"Over-expression, purification, and kinetic analysis of Mycobacterium tuberculosis WecA.","authors":"Yishu Zhao, Haiying Jia, Yan Wang, Shanshan Sha, Dong An, Shufeng Yang, Lei Qian, Yufang Ma, Liming Xu","doi":"10.1080/14756366.2025.2610028","DOIUrl":"10.1080/14756366.2025.2610028","url":null,"abstract":"The N-acetylglucosamine-1-phosphate transferase (WecA)is a potential target for developing anti-tuberculosis drugs, due to its critical role in the synthesis of mycobacterial cell wall. The enzymatic study of WecA and the discovery of WecA inhibitors are therefore justified. However, WecA is a membrane protein with 11 transmembrane domains, making it difficult to be obtained, and even more difficult to perform activity studies. In order to gain sufficient WecA protein for activity investigation, the Escherichia coli (E. coli) Lemo21(DE3) strain was utilised in this study. The expression level of WecA was precisely regulated by T7 lysozyme. Purified WecA was obtained by affinity chromatography and identified by mass spectrometry. The kinetic properties of WecA were determined based on the detection of the product UMP. In addition, tunicamycin proved to be a competitive inhibitor. These results will lay theoretical foundations for the elucidation of WecA catalytic mechanism and the development of WecA inhibitors.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"41 1","pages":"2610028"},"PeriodicalIF":5.4,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12784632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145933639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of novel and highly potent XIAP-targeted peptide inhibitors using virtual screening. 使用虚拟筛选发现新型高效的xiap靶向肽抑制剂。

IF 5.4 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2026-12-01 Epub Date: 2026-01-21 DOI: 10.1080/14756366.2026.2613518

Xiaoliang Wang, Mengting Lou, Yuting Wang, Miao-Miao Niu, Dongli Zhang

{"title":"Discovery of novel and highly potent XIAP-targeted peptide inhibitors using virtual screening.","authors":"Xiaoliang Wang, Mengting Lou, Yuting Wang, Miao-Miao Niu, Dongli Zhang","doi":"10.1080/14756366.2026.2613518","DOIUrl":"10.1080/14756366.2026.2613518","url":null,"abstract":"Lung cancer, a globally prevalent fatal malignancy, remains a major therapeutic challenge. X-linked inhibitor of apoptosis protein (XIAP) is overexpressed in various cancers, driving uncontrolled proliferation, while its specific inhibition suppresses tumour growth. Through virtual screening, we identified five novel candidate peptides (Peptides 1-5) with picomolar-level inhibitory activity. Peptide-5 showed the highest binding affinity (Kd = 10.2 ± 0.5 pM), and FP assay indicated that Peptide-5 competitively binds the BIR3 domain of XIAP against caspase-9. Molecular dynamics simulations confirmed the structural stability of its complex with XIAP. Meanwhile, Peptide-5 showed good serum and metabolic stability, as well as favourable cellular permeability. Notably, Peptide-5 exhibited potent antiproliferative activity against various tumour cells with no obvious toxicity to normal cells. Peptide-5 potentially activates apoptotic signalling through modulating the Bcl-2/Bax mRNA expression. In summary, our study confirms that Peptide-5 is a highly potent and promising XIAP-targeted inhibitor for the treatment of cancer.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"41 1","pages":"2613518"},"PeriodicalIF":5.4,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12829411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146018865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification and biological evaluation of benzimidazole-based compounds as novel TGFβR1 inhibitors. 以苯并咪唑为基础的新型TGFβR1抑制剂的鉴定和生物学评价。

IF 5.4 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2026-12-01 Epub Date: 2026-01-21 DOI: 10.1080/14756366.2025.2600746

Hui-Ju Tseng, Yi-Wen Wu, Yan-Ling Chen, Tony Eight Lin, Yu-Ting Fang-Chin, Yueh-Lin Wu, Tzu-Ying Sung, Shih-Chung Yen, Jui-Hua Hsieh, Kai-Cheng Hsu, Shiow-Lin Pan

{"title":"Identification and biological evaluation of benzimidazole-based compounds as novel TGFβR1 inhibitors.","authors":"Hui-Ju Tseng, Yi-Wen Wu, Yan-Ling Chen, Tony Eight Lin, Yu-Ting Fang-Chin, Yueh-Lin Wu, Tzu-Ying Sung, Shih-Chung Yen, Jui-Hua Hsieh, Kai-Cheng Hsu, Shiow-Lin Pan","doi":"10.1080/14756366.2025.2600746","DOIUrl":"10.1080/14756366.2025.2600746","url":null,"abstract":"TGF-β promotes progression and metastasis in later stages of tumour development, and inhibitors targeting TGF-β or its receptor have faced clinical limitations due to toxicity and poor selectivity. This study aimed to identify novel TGFβR1 inhibitors by screening the ChemDiv database using a structure-based virtual screening approach. Among the top-ranked compounds, 3282-0487 showed the highest potency. Its analogues were further evaluated, leading to four potent TGFβR1 inhibitors with sub-micromolar IC50 values. Molecular docking confirmed favourable binding interactions, and structure-activity relationship analysis highlighted key structural features contributing to inhibitory activity. Among these, compound 3282-0486 demonstrated the lowest IC50 values against colorectal cancer cells, inducing apoptosis and dose-dependent anti-migration effects. Its efficacy was further supported by changes in downstream TGFβR1 signalling, including p-Smad2, EMT markers, and PARP1 cleavage. Additionally, compound 3282-0486 exhibited selectivity for TGFβR1. Overall, these findings support compound 3282-0486 as a promising TGFβR1 inhibitor with therapeutic potential.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"41 1","pages":"2600746"},"PeriodicalIF":5.4,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12829415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146018877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of novel coumarin-containing triazolo[1,5-a]pyrimidine derivatives as potent ABCB1 inhibitor for modulation of multidrug resistance. 新型香豆素类三唑[1,5-a]嘧啶衍生物作为ABCB1多药耐药调控抑制剂的发现。

IF 5.4 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2026-12-01 Epub Date: 2026-02-19 DOI: 10.1080/14756366.2026.2629074

Nan Ye Hmone, Xuefei Tian, Dandan Zhou, Zhiyi Min, Yingxue Zhao, Shuai Wang, Fen-Er Chen, Ziyu Wang, Xuyao Zhang

{"title":"Discovery of novel coumarin-containing triazolo[1,5-a]pyrimidine derivatives as potent ABCB1 inhibitor for modulation of multidrug resistance.","authors":"Nan Ye Hmone, Xuefei Tian, Dandan Zhou, Zhiyi Min, Yingxue Zhao, Shuai Wang, Fen-Er Chen, Ziyu Wang, Xuyao Zhang","doi":"10.1080/14756366.2026.2629074","DOIUrl":"10.1080/14756366.2026.2629074","url":null,"abstract":"ABCB1-mediated drug efflux is a key determinant of multidrug resistance (MDR) in cancer. To overcome this mechanism, a series of thiol-substituted aminocoumarin-derived, coumarin-containing triazolo[1,5-a]pyrimidine derivatives (5a-5s) was synthesised, and compound 5r (NYH-707) was identified as the most potent ABCB1 inhibitor. NYH-707 markedly restored paclitaxel sensitivity in SW620/Ad300 MDR cells, reducing the IC50 from 4.55 ± 0.73 µM to 0.011 ± 0.002 µM (reversal factor = 413.6). Molecular docking predicted strong binding (-9.7 kcal/mol) through hydrogen bonding with LYS-826 and SER-880 and π-π stacking with PHE-994. CETSA confirmed direct ABCB1 engagement, while drug-accumulation assays demonstrated inhibition of ABCB1-mediated efflux. In vivo, co-administration of NYH-707 and paclitaxel significantly suppressed SW620/Ad300 xenograft growth without detectable systemic toxicity. These findings indicate that NYH-707 acts as a potent and selective ABCB1 modulator capable of reversing MDR likely by modulating ABCB1 conformational dynamics, thereby enhancing chemotherapeutic efficacy in resistant tumours.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"41 1","pages":"2629074"},"PeriodicalIF":5.4,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12922422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146227069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of prolyl-tRNA synthetase and efflux pumps as a dual-targeting strategy against multidrug-resistant bacteria. 抑制脯氨酸- trna合成酶和外排泵对多重耐药细菌的双重靶向策略。

IF 5.4 2区医学

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2026-12-01 Epub Date: 2026-03-18 DOI: 10.1080/14756366.2026.2640718

Cristiane Tambascia, Jaqueline Cristina Silva, Barbara Carvalho Dos Reis, Camila Fernanda Silva Camilo, Carlos Abrunhosa Tairum Junior, Thais Hancio, Valquiria Graia Correia, Ronaldo Aloise Pilli, Andre Schützer de Godoy, Benoît Laleu, Maurício Luís Sforça, Silvana Aparecida Rocco, Celso Eduardo Benedetti, Gustavo Fernando Mercaldi

{"title":"Inhibition of prolyl-tRNA synthetase and efflux pumps as a dual-targeting strategy against multidrug-resistant bacteria.","authors":"Cristiane Tambascia, Jaqueline Cristina Silva, Barbara Carvalho Dos Reis, Camila Fernanda Silva Camilo, Carlos Abrunhosa Tairum Junior, Thais Hancio, Valquiria Graia Correia, Ronaldo Aloise Pilli, Andre Schützer de Godoy, Benoît Laleu, Maurício Luís Sforça, Silvana Aparecida Rocco, Celso Eduardo Benedetti, Gustavo Fernando Mercaldi","doi":"10.1080/14756366.2026.2640718","DOIUrl":"10.1080/14756366.2026.2640718","url":null,"abstract":"Aminoacyl-tRNA synthetases have been widely exploited as targets for antiparasitic and antifungal inhibitors; however, they have received little attention as targets in multidrug-resistant (MDR) bacteria. Here we describe the biochemical characterisation of Prolyl-tRNA synthetase from Klebsiella pneumoniae (KpProRS), highlighting its ligase and proofreading activities. Distinct classes of ProRS inhibitors were evaluated against KpProRS but only halofuginone (HF) strongly modulated KpProRS activity. A new HF analog (Cpd-6) was developed and exhibited superior inhibitory activity against KpProRS relative to HF but low efficacy against MDR K. pneumoniae, despite good antimicrobial activity against Escherichia coli and Staphylococcus aureus. Further studies revealed that Cpd-6 resistance in K. pneumonia is mainly mediated by AcrAB efflux pump activity, which could be counteracted by efflux pump inhibitors. These findings therefore reinforce KpProRS as a target for antimicrobial development and highlight the therapeutic potential of combining HF analogues with efflux pump inhibitors to fight Gram-negative MDR pathogens.","PeriodicalId":15769,"journal":{"name":"Journal of Enzyme Inhibition and Medicinal Chemistry","volume":"41 1","pages":"2640718"},"PeriodicalIF":5.4,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13003883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147474011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0