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development of BACE2-IN-1/tranylcypromine-based compounds to induce steroidogenesis-dependent neuroprotection

Biomedicine and pharmacotherapy 2025年 183卷 117851-117851页

作者： Banerjee, Suddhasatwa Hsu, Ying-Ting Nguyen, duc-Hieu Yeh, Shiu-Hwa Liou, Ke-Chi Liu, Jr-Jiun Liou, Jing-Ping Chuang, Jian-Ying School of Pharmacy Taipei Medical University Taipei 11031 Taiwan Ph.D. Program in Medical Neuroscience Taipei Medical University and National Health Research Institutes Taipei 11031 Taiwan Institute of Biotechnology and Pharmaceutical Research National Health Research Institutes Miaoli County 35053 Taiwan TMU Research Center for Drug Discovery Taipei Medical University Taipei 11031 Taiwan Ph.D. Program in Drug Discovery and Development Industry College of Pharmacy Taipei Medical University Taipei 110 Taiwan International Master Program in Medical Neuroscience Taipei Medical University New Taipei City 23564 Taiwan TMU Research Center of Neuroscience Taipei Medical University Taipei 11031 Taiwan Department of Biomedical Science and Environmental Biology Kaohsiung Medical University Kaohsiung 80780 Taiwan

Traumatic brain injury (TBI) constitutes a significant burden on global healthcare systems, especially affecting younger populations, where it is a leading cause of disability and mortality. Current treatments for TBI mainly focus on preventing further brain damage and controlling symptoms. However, despite these approaches, several clinical needs remain unmet. Revelations from single-cell RNA sequencing (scRNA-seq) performed to determine cell-type heterogeneity and gene expression changes in brain tissue indicated that brain trauma increases the expression of lysine-specific demethylase 1 (LSd1) and secretase 2 (BACE2). To capitalize on this finding, a medicinal chemistry campaign was conducted to pragmatically insert tranylcypromine, an LSd1 inhibitor, into a carefully designed BACE2 inhibitory template (BACE2-IN-1). Additionally, tranylcypromine was structurally modified to enhance the effects of LSd1 inhibition in TBI. As a result, a tractable neuroprotective agent, BACE2-IN-1/tranylcypromine-based compound 4, was identified, showing potential to maintain Neuro-2a cell survival by alleviating mitochondrial damage after oxidative stress. Compound 4 also restored TBI-mediated inhibition of the cholesterol biosynthetic pathway (mevalonate pathway) and damage of redox metabolism, increasing neuroprotective effects. Furthermore, behavioral assays, including nest-building and cognitive performance tests, demonstrated significant improvement in mice post-TBI following treatment with compound 4. Taken together, the outcomes of this study validate the favorable effects of inhibiting LSd1 and beta-secretase in mitigating mitochondrial stress and promoting neurometabolic recovery in TBI. These findings pave the way for the development of rationally designed inhibitors as promising neuroprotective agents, potentially addressing unmet clinical needs in TBI treatment. © 2025 The Authors

关键词： Beta-secretase LSd1 Oxidative stress Sterol biosynthesis Tranylcypromine Traumatic brain injury

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Prediction tools for assessing functional impacts of gene mutations in Clear Cell Renal Cell Carcinoma: A comparative study

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Computers in Biology and Medicine 2025年第Pt A期192卷 110187-110187页

作者： Yang, Cheng-Hong Lin, Guan-Cheng Wu, Chih-Hsien Chen, Jin-Bor Chuang, Li-Yeh Department of Information Management Tainan University of Technology Tainan Taiwan Department of Electronic Engineering National Kaohsiung University of Science and Technology Kaohsiung Taiwan Drug Development and Value Creation Research Center Kaohsiung Taiwan Ph. D. Program in Biomedical Engineering Kaohsiung Medical University Kaohsiung Taiwan Division of Nephrology Department of Internal Medicine Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Taiwan Department of Chemical Engineering & Institute of Biotechnology and Chemical Engineering I-Shou University Kaohsiung Taiwan Taiwan

Renal cell carcinoma (RCC) is a well-known malignancy characterized by specific gene mutations that elevate its occurrence. It can be categorized into clear cell RCC (ccRCC), papillary RCC, and chromophobe RCC, which account for approximately 85 % of all primary RCC cases. The mutations typically involve single-nucleotide variants (SNVs) that lead to amino acid substitutions, which influence various biological functions, including gene expression. Therefore, predicting the functional consequences of RCC-related single-nucleotide polymorphisms (SNPs), including substitutions, insertions, deletions, and duplications, is crucial for the effective clinical management of RCC. In recent years, the accessibility and popularity of tools for predicting SNP functional variations have grown, especially in research concerning the potential risks associated with key gene mutations in cancer. Accordingly, this study focused on commonly mutated genes in ccRCC, namely VHL, BAP1, PBRM1, and SETd2. Public data from sources such as The Cancer Genome Atlas and the National Center for biotechnology Information were used to identify 61 gene mutation positions. Nine nonsynonymous mutation prediction tools were used for analysis, namely SIFT, Polyphen-2, Mutation Assessor, Fathmm, MutPred, CHASM, Revel, Provean, and SNP&GO. The tools were evaluated by their statistical performance, prediction distribution, and receiver operating characteristic curves. The three tools with the highest accuracy for predicting the functional consequences of mutations in the four frequently mutated genes associated with ccRCC were SIFT (accuracy of 0.75), Provean (0.7), and Polyphen-2 (0.69). These findings offer valuable insights into predicting ccRCC-related gene mutation effects, but further research and validation are essential to support their clinical applications. © 2025

关键词： Transcription

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Umbilical cord-derived mesenchymal stem cells secretomes promote embryo development and implantation

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Life Sciences 2025年 374卷 123693页

作者： Teerapong, Prompunya Yang, Yuan-Ting Bhargava Sreerangaraja Urs, dilip Liu, Jun-Jen Kao, Shu-Huei Ph. D. Program in Medical Biotechnology College of Medical Science and Technology Taipei Medical University Taipei 110 Taiwan Veterinary Research and Development Center-Lower Northern Region National Institute of Animal Health Bangkok 10900 Thailand Biomedical Department High-Tek Harness Enterprise Co. Ltd. Taipei 115 Taiwan School of Medical Laboratory Science and Biotechnology College of Medical Science and Technology Taipei Medical University Taipei 110 Taiwan Center for Reproductive Medicine Department of Obstetrics and Gynecology Taipei Medical University Hospital Taipei 110 Taiwan

Aims: Successful implantation relies on high-quality blastocysts, uterine receptivity, and effective embryo-endometrium communication. This study investigated the effects of umbilical cord-derived mesenchymal stem cells (UC-MSC) secretomes on embryo development and implantation. Main methods: Trophoblastic spheroids and murine embryos were used to evaluate the impact of UC-MSC secretomes. Embryos obtained through superovulation were cultured in vitro and divided into five groups: a control group and four experimental groups treated with varying concentrations of UC-MSC secretomes (2.5, 5, 10, and 50 μg/mL). Embryo development competence and implantation potential were assessed in each group, and the expression levels of related genes were analyzed. Key findings: Supplementation with UC-MSC secretomes significantly enhanced trophoblast cell migration. It also stimulated endometrial cell proliferation and upregulated key implantation-related genes (LIF, LIFR, VEGFA, ITGB3, and ITGAV), improving endometrial receptivity and adhesion in trophoblastic spheroid co-cultures. While morulation rates of murine embryos remained unchanged, UC-MSC secretomes supplement significantly increased blastulation, pluripotency gene expression, and hatching rates. Supplementation with 10 and 50 μg/mL significantly increased blastocyst diameter and blastomere number, as well as embryo adhesion, outgrowth areas, and implantation rates. Additionally, growth factor analysis showed elevated VEGF-A and PdGF-AA levels in the culture media. Significance: This study demonstrates that UC-MSC secretomes enhance both embryo development and endometrial cell function, facilitating implantation potential. These findings suggest their potential utility in supporting preimplantation embryos and improving maternal endometrial receptivity in ART. © 2025 The Authors

关键词： Embryo development Embryo implantation Secretomes Umbilical cord mesenchymal stem cells

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Harnessing the bishomolithocholic acid scaffold for selective sialyltransferase inhibition: A targeted approach to suppress breast cancer metastasis

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European Journal of Medicinal Chemistry 2025年 292卷 117674页

作者： Perez, Ser John Lynon P. Hsu, Zih-Fan Chang, Tzu-Ting Chen, Chia-Ling Li, Wen-Shan Institute of Chemistry Academia Sinica Taipei 115 Taiwan Department of Applied Chemistry National Yang Ming Chiao Tung University Hsinchu 300 Taiwan Sustainable Chemical Science and Technology Taiwan International Graduate Program Academia Sinica Taipei 115 Taiwan Biomedical Translation Research Center Academia Sinica Taipei 115 Taiwan Department of Chemistry National Taiwan Normal University Taipei 116 Taiwan Department of Medicinal and Applied Chemistry College of Life Science Kaohsiung Medical University Kaohsiung 807 Taiwan Ph.D. Program in Drug Discovery and Development Industry College of Pharmacy Taipei Medical University Taipei 110 Taiwan Doctoral Degree Program in Marine Biotechnology National Sun Yat-Sen University Kaohsiung 804 Taiwan

ST6GAL1 plays a crucial role in the progression of triple-negative breast cancer (TNBC), highlighting its potential as a therapeutic target for this aggressive cancer subtype. due to the high metastatic potential of TNBC and the limitations of current therapies, selective and potent ST6GAL1 inhibitors are urgently needed. In this study, a scaffold-hopping approach from lithocholic acid to bishomolithocholic acid successfully led to the discovery of novel ST6GAL1 inhibitors, SPP-037 and HZF01, with enhanced biological activity and selectivity. Both compounds significantly inhibited MdA-MB-231 cell migration, HUVEC tube formation, tumor growth, and metastasis in vitro and in vivo. Molecular docking studies revealed key interactions between the ST inhibitors and ST6GAL1, supporting their enhanced selectivity and binding affinity. Additionally, SPP-037 and HZF01 were found to block integrin α2,6-sialylation, disrupting integrin activation and downstream signaling pathways involving the phosphorylation of focal adhesion kinase (FAK) and paxillin, which are critical for cell migration. These results underscore the potential of targeting ST6GAL1 to suppress tumor progression and metastasis, offering a promising avenue for treating aggressive breast cancer. © 2025 Elsevier Masson SAS

关键词： Bishomolithocholic acid Breast cancer metastasis Integrin-FAK-Paxillin axis N-glycan sialylation Sialyltransferase inhibitor ST6GAL1

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7S,8R-dihydroxydeepoxysarcophytoxide: A natural dihydrofuranocembranoid from the octocoral Sarcophyton stellatum

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phytochemistry Letters 2024年 63卷 14-17页

作者： Sheu, Jyh-Horng Zheng, Li-Guo Chen, You-Ying Chien, Su-Ying Sung, Ping-Jyun Department of Marine Biotechnology and Resources National Sun Yat-sen University Chinese Medicine Research and Development Center China Medical University Hospital National Museum of Marine Biology and Aquarium Instrumentation Center National Taiwan University Graduate Institute of Natural Products Kaohsiung Medical University Ph.D. Program in Pharmaceutical Biotechnology Fu Jen Catholic University

Chemical screening of the octocoral Sarcophyton stellatum led to the isolation of a natural dihydrofuranocembranoid, 7S,8R-dihydroxydeepoxysarcophytoxide (1). Single-crystal X-ray diffraction analysis was conducted to determine the absolute configuration of 1, and its structure was confirm using two-dimensional NMR experiments and a literature review. dihydrofuranocembranoid 1 actively enhanced alkaline phosphatase activity. © 2024 phytochemical Society of Europe

关键词： Absolute configuration Alkaline phosphatase dihydrofuranocembranoid Sarcophytoxide

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Computer-aided drug discovery of a dual-target inhibitor for ovarian cancer: therapeutic intervention targeting CdK1/TTK signaling pathway and structural insights in the NCI-60

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Computers in Biology and Medicine 2025年 193卷

作者： Sung-Ling Tang Maryam Rachmawati Sumitra Yu-Cheng Kuo Han-Lin Hsu Muhamad Ansar Sheng-Liang Huang Shih-Yu Lee Hong-Jaan Wang Bashir Lawal Alexander T.H. Wu Lung-Ching Chen Hsu-Shan Huang School of Pharmacy National Defense Medical Center Taipei 11490 Taiwan PhD Program for Cancer Molecular Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei 11031 Taiwan Graduate Institute of Cancer Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei 11031 Taiwan Department of Pharmacology School of Medicine College of Medicine Taipei Medical University Taipei 11031 Taiwan School of Post-Baccalaureate Chinese Medicine College of Chinese Medicine China Medical University Taichung 40604 Taiwan Graduate Institute of Clinical Medicine Taipei Medical University Taipei 11031 Taiwan Division of Pulmonary Medicine Department of Internal Medicine Wanfang Hospital Taipei Medical University Taipei 11031 Taiwan Ph.D. Program in the Clinical Drug Development of Herbal Medicine Taipei Medical University Taipei 110301 Taiwan Graduate Institute of Aerospace and Undersea Medicine National Defense Medical Center Taipei 11490 Taiwan UPMC Hillman Cancer Center University of Pittsburgh Pittsburgh PA USA Ph.D. Program of Translational Medicine College of Science and Technology Taipei Medical University Taipei 11031 Taiwan Division of Cardiology Department of Internal Medicine Shin Kong Wu Ho-Su Memorial Hospital Taipei 11101 Taiwan Ph.D. Program in Biotechnology Research and Development College of Pharmacy Taipei Medical University Taipei 11031 Taiwan

Ovarian cancer remains the third most prevalent and deadliest gynecologic malignancy worldwide, with most patients eventually developing resistance to platinum-based chemotherapy. This highlights a critical unmet need for innovative multitargeted therapies to address current treatment challenges. In this study, we identified 35 differentially expressed genes (dEGs) through integrated analysis of four GEO ovarian cancer datasets, with validation using TCGA data. Gene Ontology (GO) and KEGG enrichment analyses highlighted key tumor-associated pathways, and protein–protein interaction (PPI) network modeling prioritized CdK1 and TTK as high-value therapeutic targets. We evaluated the association between molecular genomic features and drug responses across the NCI-60 ovarian cancer cell line panel (IGROV1, OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, NCI/AdR-RES, and SK-OV-3), using a series of salicylanilide-derived compounds and four FdA-approved drugs (cabozantinib, paclitaxel, rapamycin, and niclosamide) from the NCI developmental Therapeutics program (dTP). Among these, NSC765690 (MCC22) emerged as the most promising candidate. It demonstrated potent antiproliferative activity, high target selectivity, and strong binding affinity to both CdK1 and TTK. Multi-omics integration, combined with AI-driven network modeling, further elucidated NSC765690's mechanism of action and its relevance to ovarian cancer pathogenesis. Additionally, AdMET and pharmacokinetic profiling confirmed its favorable drug-like properties and low predicted toxicity. Collectively, these findings establish NSC765690 as a potent dual-target inhibitor and exemplify a rational, data-driven drug discovery pipeline for overcoming chemotherapy resistance in ovarian cancer.

关键词： Ovarian cancer dual-target small molecule inhibitor Molecular docking NCI-60 panel Machine learning Molecular dynamics simulations OC ovarian cancer ML machine learning NLP natural language processing dEGs differentially Expressed Genes PPI Protein-Protein Interaction GEO Gene Expression Omnibus GO Gene Ontology IPA Ingenuity Pathway Analysis TCGA The Cancer Genome Atlas KEGG Kyoto Encyclopedia of Genes and Genomes GO-BP Gene Ontology-Biological Process dTP developmental Therapeutics program NCI National Cancer Institute CC Cellular Component MF Molecular Functions IHC immunohistochemical FdR false discovery rate BBB Blood brain barrier 3d three-dimensional MdS molecular dynamics simulation analysis RMSF analysis Root Mean Square Fluctuation analysis CdKs cyclin-dependent kinases TTK threonine and tyrosine kinase CNS central nervous system OS overall survival CSC cancer stem cells AI artificial intelligence SRB sulforhodamine B assay AdMET absorption, distribution, metabolism, excretion, and toxicity HPA human protein atlas WES whole exome sequencing MdR multidrug resistance HGSOC high-grade serous ovarian cancer TKI tyrosine kinase inhibitor SAC spindle assembly checkpoint HRR homologous recombination repair HRd homologous recombination deficiency

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Unlocking the potential of bacterial cellulose: synthesis, functionalization, and industrial impact

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International Journal of Biological Macromolecules 2025年第Pt 3期311卷 143951页

作者： Kumaravel, Ashokkumar Lin, Shin-Ping Santoso, Shella Permatasari Shanmugasundaram, Saranya Hsu, Hsien-Yi Hsieh, Chang-Wei Chou, Yu-Chieh Lin, Hui-Wen Cheng, Kuan-Chen Institute of Food Science and Technology National Taiwan University Daan District Taipei10617 Taiwan School of Food Safety Taipei Medical University 250 Wu-Hsing Street Taipei11031 Taiwan Ph.D. Program in Drug Discovery and Development Industry Taipei Medical University 250 Wu-Hsing Street Taipei11031 Taiwan Chemical Engineering Master Program Widya Mandala Surabaya Catholic University Kalijudan 37 Surabaya60114 Indonesia Collaborative Research Center for Zero Waste and Sustainability Widya Mandala Surabaya Catholic University Kalijudan 37 Surabaya60114 Indonesia Department of Chemical Engineering Faculty of Engineering Widya Mandala Catholic University Surabaya Kalijudan 37 Surabaya60114 Indonesia Department of Chemical Engineering University of Ulsan 93 Daehak-ro Nam-gu Ulsan44610 Korea Republic of City University of Hong Kong Kowloon Tong Hong Kong Shenzhen Research Institute of City University of Hong Kong Shenzhen518057 China Department of Food Science and Biotechnology National Chung-Hsing University Taichung City40227 Taiwan Department of Food Science National Ilan University Yilan City260007 Taiwan Institute of Medicine Chung Shan Medical University Taichung40201 Taiwan Department of Medical Research Chung Shan Medical University Hospital Taichung40201 Taiwan Institute of Biotechnology National Taiwan University 1 Roosevelt Rd. Sec. 4 Taipei10607 Taiwan Department of Optometry Asia University 500 Lioufeng Rd. Wufeng Taichung41350 Taiwan Department of Medical Research China Medical University Hospital China Medical University 91 Hsueh-Shih Road Taichung40402 Taiwan Department of Food Science Fu Jen Catholic University 510 Zhongzheng Rd. Xinzhuang Dist. New Taipei City242062 Taiwan

In recent years, bacterial cellulose (BC), a crystalline and nanoscale fibrillar polymer, has garnered significant interest due to its superior physical, chemical, and mechanical properties compared to plant cellulose. Inherent features of BC, which include high biodegradability, mechanical strength, and biocompatibility, make it a suitable material for use in a wide variety of applications, particularly in the domains of biomedicine and environmental science. However, realizing its full potential requires targeted chemical or physical modifications. Recent developments have focused on in-situ and ex-situ BC modification for various applications. Incorporating functional compounds into cellulose during BC synthesis enhances its strength and functional properties. Additionally, the material properties of BC, such as water content, thermal stability, and antibacterial capabilities, can be enhanced through post-synthesis modifications, including chemical acetylation, phosphorylation, and integration with other biopolymers. Currently, the applicability of BC is being improved using new modification techniques, which involve genetically engineered strains to enhance polymer characteristics and market potential. The review highlights recent advancements in BC research and novel modification strategies that enhance its applications in advanced biomedical engineering and sustainable packaging. © 2025

关键词： Acetylation

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Total synthesis and metabolic stability of hispidulin and its d-Labelled derivative

Total synthesis and metabolic stability of hispidulin and it...

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第11届世界华人药物化学研讨会（ISCMC 2018）

作者： Liangchi Chen Kaicheng Hsu Lihchu Chiou Huiju Tseng Weijan Huang Graduate Institute of Pharmacognosy College of PharmacyTaipei Medical University School of Pharmacy College of PharmacyTaipei Medical University Graduate Institute of Cancer Biology and Drug Discovery College of Medical Science and TechnologyTaipei Medical University Graduate Institute of Brain and Mind Sciences College of MedicineTaiwan University Graduate Institute of Pharmacology College of MedicineTaiwan University Ph.D.Program in Biotechnology Research and Development College of PharmacyTaipei Medical University Ph.D.Program for the Clinical Drug Discovery from Botanical Herbs College of PharmacyTaipei Medical University School of Pharmacy “Defense Medical Center”

Hispidulin is a naturally occurring flavone known to have various central nervous system(CNS) *** synthetic approaches to synthesizing hispidulin have proven unsatisfactory due to their low feasibility and poor overall *** solve these problems,this study developed a novel scheme for synthesizing hispidulin,which had an improved overall yield as well as more concise reaction steps compared to previous methods ***,using the same synthetic strategy,d-labelled hispidulin was synthesized to investigate its metabolic stability against human liver *** work may produce *** entities for enriching the library of hispidulin-derived compounds.

关键词： hispidulin total synthesis flavone microsome stability deuterium-labelled compound

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Crystal structure revision of the natural 3 β ,11-dihydroxy-9,11-secosteroids bearing a 5,6-epoxy group by single-crystal X-ray diffraction and NMR data

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Journal of Molecular Structure 2025年 1342卷

作者： Jyh-Horng Sheu Atallah F. Ahmed You-Ying Chen Li-Guo Zheng Su-Ying Chien Yen-Ju Tseng Jui-Hsin Su Ping-Jyun Sung Department of Marine Biotechnology and Resources National Sun Yat-sen University Kaohsiung 804201 Taiwan Graduate Institute of Natural Products Kaohsiung Medical University Kaohsiung 807378 Taiwan Department of Medical Research China Medical University Hospital China Medical University Taichung 404394 Taiwan Department of Pharmacognosy College of Pharmacy King Saud University Riyadh 11451 Saudi Arabia Department of Pharmacognosy Faculty of Pharmacy Mansoura University Mansoura 35516 Egypt National Museum of Marine Biology and Aquarium Pingtung 944401 Taiwan Instrumentation Center National Taiwan University Taipei 106319 Taiwan Chinese Medicine Research and Development Center China Medical University Hospital China Medical University Taichung 404394 Taiwan Ph. D. Program in Pharmaceutical Biotechnology Fu Jen Catholic University New Taipei City 242062 Taiwan Department of Biochemistry and Molecular Medicine National Dong Hwa University Hualien 974301 Taiwan

A comprehensive structural analysis of a reported natural product, previously identified as 3 β ,11-dihydroxy-5 β ,6 β -epoxy-24-methylene-9,11-secocholestan-9-one ( 1 ) and reisolated from the Taiwanese octocoral Sinularia lochmodes, was conducted. Reanalysis of the NMR spectra together with X-ray crystallographic data, led to the revision of this compound from structue 1 to its stereoisomer, 3 β ,11-dihydroxy-5 α ,6 α -epoxy-24-methylene-9,11-secocholestan-9-one ( 2 ). Based on the NMR data of 2 , several reported 3 β ,11-dihydroxy-9-oxo-9,11-secosteroids structures possessing 5,6-epoxy group should be revised. This study also provides the relationship between the 1 H/ 13 C NMR spectroscopic data and the absolute configurations of the 9,11-secosteroids possessing either 5 α ,6 α - or 5 β ,6 β -epoxy group.

关键词： Nuclear magnetic resonance spectroscopy

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Structure-guided identification and characterization of potent inhibitors targeting phoP and MtrA to combat mycobacteria

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Computational and Structural biotechnology Journal 2024年 23卷 1477-1488页

作者： Su, Han-Li Lai, Shu-Jung Tsai, Keng-Chang Fung, Kit-Man Lung, Tse-Lin Hsu, Hsing-Mien Wu, Yi-Chen Liu, Ching-Hui Lai, Hui-Xiang Lin, Jiun-Han Tseng, Tien-Sheng Department of Emergency Medicine Ditmanson Medical Foundation Chia-Yi Christian Hospital Chiayi City600 Taiwan Graduate Institute of Biomedical Sciences China Medical University Taichung Taiwan Research Center for Cancer Biology China Medical University Taichung Taiwan National Research Institute of Chinese Medicine Ministry of Health and Welfare Taipei Taiwan Ph.D. Program in Medical Biotechnology College of Medical Science and Technology Taipei Medical University Taipei Taiwan Academia Sinica Taipei11529 Taiwan Institute of Molecular Biology National Chung Hsing University Taichung Taiwan Department of Industrial Technology Ministry of Economic Affairs Taipei Taiwan Food Industry Research and Development Institute Hsinchu City Taiwan

Mycobacteria are causative agents of tuberculosis (TB), which is a global health concern. drug-resistant TB strains are rapidly emerging, thereby necessitating the urgent development of new drugs. Two-component signal transduction systems (TCSs) are signaling pathways involved in the regulation of various bacterial behaviors and responses to environmental stimuli. Applying specific inhibitors of TCSs can disrupt bacterial signaling, growth, and virulence, and can help combat drug-resistant TB. We conducted a comprehensive pharmacophore-based inhibitor screening and biochemical and biophysical examinations to identify, characterize, and validate potential inhibitors targeting the response regulators phoP and MtrA of mycobacteria. The constructed pharmacophore model phar-PR-n4 identified effective inhibitors of formation of the phoP–dNA complex: ST132 (IC50 = 29 ± 1.6 µM) and ST166 (IC50 = 18 ± 1.3 µM). ST166 (Kd = 18.4 ± 4.3 μM) and ST132 (Kd = 14.5 ± 0.1 μM) strongly targeted phoP in a slow-on, slow-off manner. The inhibitory potency and binding affinity of ST166 and ST132 for MtrAC were comparable to those of phoP. Structural analyses and molecular dynamics simulations revealed that ST166 and ST132 mainly interact with the α8-helix and C-terminal β-hairpin of phoP, with functionally essential residue hotspots for structure-based inhibitor optimization. Moreover, ST166 has in vitro antibacterial activity against Macrobacterium marinum. Thus, ST166, with its characteristic 1,2,5,6-tetrathiocane and terminal sulphonic groups, has excellent potential as a candidate for the development of novel antimicrobial agents to combat pathogenic mycobacteria. © 2024 The Authors

关键词： Antimicrobial agents

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