Bioorganic & Medicinal Chemistry Letters最新文献

英文中文

Phenyl urea based adjuvants for β-lactam antibiotics against methicillin resistant Staphylococcus aureus

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-03-03 DOI: 10.1016/j.bmcl.2025.130164

Hailey S. Butman , Monica A. Stefaniak , Danica J. Walsh , Vijay S. Gondil , Mikaeel Young , Andrew H. Crow , Ansley M. Nemeth , Roberta J. Melander , Paul M. Dunman , Christian Melander

Penicillin binding protein 4 (PBP4) is essential for Staphylococcus aureus cortical bone osteocyte lacuno-canalicular network (OLCN) invasion, which causes osteomyelitis and serves as a bacterial niche for recurring bone infection. Moreover, PBP4 is also a key determinant of S. aureus resistance to fifth-generation cephalosporins (ceftobiprole and ceftaroline). From these perspectives, the development of S. aureus PBP4 inhibitors may represent dual functional therapeutics that prevent osteomyelitis, and reverse PBP4-mediated β-lactam resistance. A high-throughput screen for small molecules that inhibit S. aureus PBP4 function identified compound 1. We recently described a preliminary structure activity relationship (SAR) study on 1, identifying several compounds with increased PBP4 inhibitory activity, some of which also inhibit PBP2a. Herein, we expand our exploration of phenyl ureas as antibiotic adjuvants, investigating their activity with penicillins and additional cephalosporins against PBP2a-mediated methicillin-resistant S. aureus (MRSA). We screened the previously reported pilot library, and prepared an additional series of phenyl ureas based on compound 1. Lead compounds potentiate multiple β-lactam antibiotics, lowering minimum inhibitory concentrations (MICs) below susceptibility breakpoints, with up to 64-fold reductions in MIC.

{"title":"Phenyl urea based adjuvants for β-lactam antibiotics against methicillin resistant Staphylococcus aureus","authors":"Hailey S. Butman , Monica A. Stefaniak , Danica J. Walsh , Vijay S. Gondil , Mikaeel Young , Andrew H. Crow , Ansley M. Nemeth , Roberta J. Melander , Paul M. Dunman , Christian Melander","doi":"10.1016/j.bmcl.2025.130164","DOIUrl":"10.1016/j.bmcl.2025.130164","url":null,"abstract":"<div><div>Penicillin binding protein 4 (PBP4) is essential for <em>Staphylococcus aureus</em> cortical bone osteocyte lacuno-canalicular network (OLCN) invasion, which causes osteomyelitis and serves as a bacterial niche for recurring bone infection. Moreover, PBP4 is also a key determinant of <em>S. aureus</em> resistance to fifth-generation cephalosporins (ceftobiprole and ceftaroline). From these perspectives, the development of <em>S. aureus</em> PBP4 inhibitors may represent dual functional therapeutics that prevent osteomyelitis, and reverse PBP4-mediated β-lactam resistance. A high-throughput screen for small molecules that inhibit <em>S. aureus</em> PBP4 function identified compound <strong>1</strong>. We recently described a preliminary structure activity relationship (SAR) study on <strong>1</strong>, identifying several compounds with increased PBP4 inhibitory activity, some of which also inhibit PBP2a. Herein, we expand our exploration of phenyl ureas as antibiotic adjuvants, investigating their activity with penicillins and additional cephalosporins against PBP2a-mediated methicillin-resistant <em>S. aureus</em> (MRSA). We screened the previously reported pilot library, and prepared an additional series of phenyl ureas based on compound <strong>1</strong>. Lead compounds potentiate multiple β-lactam antibiotics, lowering minimum inhibitory concentrations (MICs) below susceptibility breakpoints, with up to 64-fold reductions in MIC.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130164"},"PeriodicalIF":2.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Bulky substrates of isoleucine 2-epimerase: α-Neopentylglycine and NV-5138

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-03-02 DOI: 10.1016/j.bmcl.2025.130160

Noa T. Sorbara , Amanda K.A. Black , Stephen L. Bearne

Isoleucine 2-epimerase from Lactobacillus buchneri (LbIleE) catalyzes the pyridoxal 5′-phosphate-dependent, reversible, racemization or epimerization of nonpolar amino acids at the C-2 position. The integral role of the enzyme in the biosynthesis of branched-chain d-amino acids makes it a potential target for the development of antimicrobial agents. Probing the hydrophobic active-site pocket with a series of alkyl boronic acids, we show that the hydrophobic pocket accommodates the neopentyl group with enhanced binding affinity relative to the sec-butyl group. Subsequently, we show that LbIleE catalyzes the racemization of l- and d-α-neopentylglycine, exhibiting binding affinities for these substrates 6- and 24-fold greater than those for l-Ile and d-allo-Ile, but with catalytic efficiencies (k_cat/K_m) reduced 46- and 27-fold, respectively. NV-5138 is a ligand of the leucine-binding site of Sestrin2, which activates the mechanistic target of rapamycin complex1 (mTORC1) and is structurally similar to α-neopentylglycine. Our demonstration that LbIleE catalyzes the racemization of l-NV-5138 (k_cat/K_m = 2.2 ± 0.2 s⁻¹ mM⁻¹), along with the fact that L. buchneri can be present in the human gut microbiome, suggests that formation of d-NV-5138 could occur in humans when l-NV-5138 is used as a pharmacological intervention for depression.

{"title":"Bulky substrates of isoleucine 2-epimerase: α-Neopentylglycine and NV-5138","authors":"Noa T. Sorbara , Amanda K.A. Black , Stephen L. Bearne","doi":"10.1016/j.bmcl.2025.130160","DOIUrl":"10.1016/j.bmcl.2025.130160","url":null,"abstract":"<div><div>Isoleucine 2-epimerase from <em>Lactobacillus buchneri</em> (<em>Lb</em>IleE) catalyzes the pyridoxal 5′-phosphate-dependent, reversible, racemization or epimerization of nonpolar amino acids at the C-2 position. The integral role of the enzyme in the biosynthesis of branched-chain <span>d</span>-amino acids makes it a potential target for the development of antimicrobial agents. Probing the hydrophobic active-site pocket with a series of alkyl boronic acids, we show that the hydrophobic pocket accommodates the neopentyl group with enhanced binding affinity relative to the sec-butyl group. Subsequently, we show that <em>Lb</em>IleE catalyzes the racemization of <span>l</span>- and <span>d</span>-α-neopentylglycine, exhibiting binding affinities for these substrates 6- and 24-fold greater than those for <span>l</span>-Ile and <span>d</span>-<em>allo</em>-Ile, but with catalytic efficiencies (<em>k</em><sub>cat</sub>/<em>K</em><sub>m</sub>) reduced 46- and 27-fold, respectively. NV-5138 is a ligand of the leucine-binding site of Sestrin2, which activates the mechanistic target of rapamycin complex1 (mTORC1) and is structurally similar to α-neopentylglycine. Our demonstration that <em>Lb</em>IleE catalyzes the racemization of <span>l</span>-NV-5138 (<em>k</em><sub>cat</sub>/<em>K</em><sub>m</sub> = 2.2 ± 0.2 s<sup>−1</sup> mM<sup>−1</sup>), along with the fact that <em>L</em>. <em>buchneri</em> can be present in the human gut microbiome, suggests that formation of <span>d</span>-NV-5138 could occur in humans when <span>l</span>-NV-5138 is used as a pharmacological intervention for depression.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130160"},"PeriodicalIF":2.5,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 1,3-Disubstituted Pyrazole derivatives as Mycobacterium tuberculosis inhibitors

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-02-28 DOI: 10.1016/j.bmcl.2025.130156

Guoquan Wan , Chao Gao , Xiaorui Zhang , Huapei Qiu , Qifan Tang , Jumei Zeng , Luoting Yu

Tuberculosis is a global epidemic caused by Mycobacterium tuberculosis, predominantly impacting underprivileged regions worldwide. Here, we identified a novel 1,3-disubstituted pyrazole derivative, compound A, that exhibits antitubercular activity through in vitro screening. Further SAR studies resulted in the identification of compounds 4c and 6b, which exhibited improved antitubercular activity, with MIC values of 5.34 and 5.04 μg/mL against H37Ra, respectively. Additionally, compounds 4c and 6b exhibited favorable safety profiles, showing no obvious toxicity to Vero, A549, and HepG2 cell lines. Our docking studies suggest that PptT may serve as one of the potential targets for these compounds. These encouraging results provide valuable insights for the development of novel structured antitubercular agents.

结核病是由结核分枝杆菌引起的全球性流行病，主要影响世界各地的贫困地区。在这里，我们通过体外筛选发现了一种新型 1,3-二取代吡唑衍生物--化合物 A，它具有抗结核活性。进一步的 SAR 研究发现了化合物 4c 和 6b，它们的抗结核活性有所提高，对 H37Ra 的 MIC 值分别为 5.34 和 5.04 μg/mL。此外，化合物 4c 和 6b 还具有良好的安全性，对 Vero、A549 和 HepG2 细胞系没有明显毒性。我们的对接研究表明，PptT 可能是这些化合物的潜在靶点之一。这些令人鼓舞的结果为开发新型结构抗结核药物提供了宝贵的启示。

引用次数: 0

Synthesis and evaluation of a targeted PET radioligand [18F]FCOB02 for monoamine oxidase B

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-02-24 DOI: 10.1016/j.bmcl.2025.130157

Zhixiong Zhang , Ge Zhang , Jingquan Xue , Yuxuan Zhang , Yu Liu , Wenjiang Yang , Jianjun Wang

Monoamine oxidase B (MAO-B) is a membrane-bound flavinase that plays an important role in the regulation of monoamine neurotransmission. Positron emission tomography (PET) provides a way to study the molecular mechanisms of MAO-B-related diseases and to evaluate the effects of drugs. In this study, we designed and synthesized [¹⁸F]FCOB02, a 4-methylcoumarin-like targeting probe.[¹⁸F]FCOB02 is straightforward to synthesize and has a high affinity for MAO-B with an IC₅₀ = 10.68 ± 3.25 nM. Successful radiolabeling with fluorine-18 was achieved, resulting in a labeling rate of 35 % along with favorable lipid solubility (log D_7.4 = 2.4). Automated radiolabelling was achieved after optimization of the conditions. The radiochemical yield was 9.6 % ± 1.2 %(n = 3) with good radiochemical purity (>98 %), good stability in saline for 4 h and high specific activity (105.08 ± 19GBq/μmol，n = 3). Biodistribution studies conducted in mice revealed significant initial brain uptake of 8.22 ± 0.86 % ID/g at 2 min post-injection, followed by rapid metabolism primarily via the liver and kidneys. Brain uptake was comparable to the same type of probe [¹⁸F]SMBT-1 (brain _2min = 7.85 % ID/g). PET-CT images of [¹⁸F]FCOB02 in SD rats showed significant differences in brain uptake before and after inhibition by the inhibitor L-deprenyl. Whole brain uptake was reduced by 20 % after inhibition, indicating specific uptake of the probe in the brain, with a 40-min brain clearance rate of 81 %. The potential utility of [¹⁸F]FCOB02 for achieving specific MAO-B imaging as well as quantitative analysis in vivo warrants further investigation regarding its clinical translational value.

{"title":"Synthesis and evaluation of a targeted PET radioligand [18F]FCOB02 for monoamine oxidase B","authors":"Zhixiong Zhang , Ge Zhang , Jingquan Xue , Yuxuan Zhang , Yu Liu , Wenjiang Yang , Jianjun Wang","doi":"10.1016/j.bmcl.2025.130157","DOIUrl":"10.1016/j.bmcl.2025.130157","url":null,"abstract":"<div><div>Monoamine oxidase B (MAO-B) is a membrane-bound flavinase that plays an important role in the regulation of monoamine neurotransmission. Positron emission tomography (PET) provides a way to study the molecular mechanisms of MAO-B-related diseases and to evaluate the effects of drugs. In this study, we designed and synthesized [<sup>18</sup>F]FCOB02, a 4-methylcoumarin-like targeting probe.[<sup>18</sup>F]FCOB02 is straightforward to synthesize and has a high affinity for MAO-B with an IC<sub>50</sub> = 10.68 ± 3.25 nM. Successful radiolabeling with fluorine-18 was achieved, resulting in a labeling rate of 35 % along with favorable lipid solubility (log <em>D</em><sub>7.4</sub> = 2.4). Automated radiolabelling was achieved after optimization of the conditions. The radiochemical yield was 9.6 % ± 1.2 %(<em>n</em> = 3) with good radiochemical purity (>98 %), good stability in saline for 4 h and high specific activity (105.08 ± 19GBq/μmol，n = 3). Biodistribution studies conducted in mice revealed significant initial brain uptake of 8.22 ± 0.86 % ID/g at 2 min post-injection, followed by rapid metabolism primarily via the liver and kidneys. Brain uptake was comparable to the same type of probe [<sup>18</sup>F]SMBT-1 (brain <sub>2min</sub> = 7.85 % ID/g). PET-CT images of [<sup>18</sup>F]FCOB02 in SD rats showed significant differences in brain uptake before and after inhibition by the inhibitor L-deprenyl. Whole brain uptake was reduced by 20 % after inhibition, indicating specific uptake of the probe in the brain, with a 40-min brain clearance rate of 81 %. The potential utility of [<sup>18</sup>F]FCOB02 for achieving specific MAO-B imaging as well as quantitative analysis in vivo warrants further investigation regarding its clinical translational value.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130157"},"PeriodicalIF":2.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143512106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, synthesis and biological evaluation of sulfur-containing tetrahydroxanthones as potential anti-tumor agents

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-02-24 DOI: 10.1016/j.bmcl.2025.130154

Huimin Zheng , Youyi Wang , Yitao Ren , Xueying Wang , Lu Sui , Hongxi Xu , Changwu Zheng

Given the rising incidence and mortality rates of cancer, the development of highly effective, low-toxicity therapeutics is critical. Xanthones, a class of natural secondary metabolites, are notable for their distinct structure and exhibit promising antitumor activity, underscoring their potential as scaffolds for drug design. Sulfur heterocycles are also valuable in the development of bioactive small molecules. Therefore, we explored the introduction of sulfur in the core structure of xanthones, leading to the synthesis of a series of sulfur-containing tetrahydroxanthones. The in vitro cytotoxicity of these compounds was evaluated using the CCK8 assay, revealing that several derivatives exhibit anti-proliferative effects against HepG2 cells. Among them, compound 4k displayed potent inhibitory activity with an IC₅₀ value of 6.08 μM and showed favorable selectivity, exhibiting low toxicity toward normal cells. Further studies demonstrated that 4k inhibited colony formation and migration of HepG2 cells, and induced apoptosis.

{"title":"Design, synthesis and biological evaluation of sulfur-containing tetrahydroxanthones as potential anti-tumor agents","authors":"Huimin Zheng , Youyi Wang , Yitao Ren , Xueying Wang , Lu Sui , Hongxi Xu , Changwu Zheng","doi":"10.1016/j.bmcl.2025.130154","DOIUrl":"10.1016/j.bmcl.2025.130154","url":null,"abstract":"<div><div>Given the rising incidence and mortality rates of cancer, the development of highly effective, low-toxicity therapeutics is critical. Xanthones, a class of natural secondary metabolites, are notable for their distinct structure and exhibit promising antitumor activity, underscoring their potential as scaffolds for drug design. Sulfur heterocycles are also valuable in the development of bioactive small molecules. Therefore, we explored the introduction of sulfur in the core structure of xanthones, leading to the synthesis of a series of sulfur-containing tetrahydroxanthones. The in vitro cytotoxicity of these compounds was evaluated using the CCK8 assay, revealing that several derivatives exhibit anti-proliferative effects against HepG2 cells. Among them, compound <strong>4</strong><strong>k</strong> displayed potent inhibitory activity with an IC<sub>50</sub> value of 6.08 μM and showed favorable selectivity, exhibiting low toxicity toward normal cells. Further studies demonstrated that <strong>4</strong><strong>k</strong> inhibited colony formation and migration of HepG2 cells, and induced apoptosis.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130154"},"PeriodicalIF":2.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery and biological evaluation of carborane-containing derivatives as TEAD auto palmitoylation inhibitors

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-02-24 DOI: 10.1016/j.bmcl.2025.130155

Chaofan Li , Yingshuang Zhang , Ziyin Zhang , Yirong Zhang , Yuxuan Song , Linyuan Wang , Changxian Yuan , Guanxiang Hao , Nan Sun , Hongjing Li , Zhiguang Zhang , Yundong He , Sinan Wang

Transcriptional enhanced associate domain (TEAD) proteins are key downstream effectors of the Hippo signaling pathway that play a crucial role in various cell processes including tissue development, regeneration, cell proliferation and cancer. TEADs contain a hydrophobic auto-palmitoylation pocket that can bind palmitic acid and stabilize TEADs from being degraded. Inhibitors targeting this palmitoylation pocket typically consist of hydrophobic pharmacophores. Carboranes is a cage-shaped molecule exhibiting superior hydrophobicity compared to adamantane or phenyl groups. Herein, we incorporated carborane into known TEAD inhibitors for better interaction with the hydrophobic palmitate pocket. Compounds 1f and 1l are identified as TEAD transcription inhibitors with strong anti-proliferation and anti-migration activities toward prostate cancer cell lines. They also significantly reduced TEAD-regulated downstream gene expressions.

{"title":"Discovery and biological evaluation of carborane-containing derivatives as TEAD auto palmitoylation inhibitors","authors":"Chaofan Li , Yingshuang Zhang , Ziyin Zhang , Yirong Zhang , Yuxuan Song , Linyuan Wang , Changxian Yuan , Guanxiang Hao , Nan Sun , Hongjing Li , Zhiguang Zhang , Yundong He , Sinan Wang","doi":"10.1016/j.bmcl.2025.130155","DOIUrl":"10.1016/j.bmcl.2025.130155","url":null,"abstract":"<div><div>Transcriptional enhanced associate domain (TEAD) proteins are key downstream effectors of the Hippo signaling pathway that play a crucial role in various cell processes including tissue development, regeneration, cell proliferation and cancer. TEADs contain a hydrophobic auto-palmitoylation pocket that can bind palmitic acid and stabilize TEADs from being degraded. Inhibitors targeting this palmitoylation pocket typically consist of hydrophobic pharmacophores. Carboranes is a cage-shaped molecule exhibiting superior hydrophobicity compared to adamantane or phenyl groups. Herein, we incorporated carborane into known TEAD inhibitors for better interaction with the hydrophobic palmitate pocket. Compounds <strong>1f</strong> and <strong>1l</strong> are identified as TEAD transcription inhibitors with strong anti-proliferation and anti-migration activities toward prostate cancer cell lines. They also significantly reduced TEAD-regulated downstream gene expressions.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130155"},"PeriodicalIF":2.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

N-alkyl substituted armeniaspirol analogs show potent antibiotic activity and have low susceptibility to resistance

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-02-21 DOI: 10.1016/j.bmcl.2025.130137

Michael G. Darnowski, Taylor D. Lanosky, Antonio D. Spada, Jason Ma, André R. Paquette, Christopher N. Boddy

The armeniaspirol family of antibiotics have been shown to inhibit the ATP-dependent proteases ClpXP and ClpYQ and to disrupt the electrical membrane potential (ΔΨ) bacterial proton motive force. The synthesis and characterization of first generation armeniaspirol analogs shows the N-alkyl group is amenable to modification. Herein we synthesize eleven second generation N-alkyl analogs and show they display excellent antibiotic potency against multiple MRSA strains and retain the ability to disrupt membrane electrical potential. We also show that it is difficult to generate resistant MRSA mutants to these new compounds, making them appealing leads for new antibiotic development.

引用次数: 0

Sensitive and reliable gastric ulcer related MicroRNA detection by bridge catalytic hairpin assembly (bCHA) mediated primer exchange reaction

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-02-21 DOI: 10.1016/j.bmcl.2025.130153

Ligong Wang , Shan Zhao , Pang Hui , Kaige Zhang

MicroRNAs (miRNA) have a significant role in the progression of gastric ulcer, and the sensitive and reliable detection of miRNAs is pivotal for the early diagnosis and treatment of gastrointestinal diseases. In this study, we developed a novel and efficient method for detecting miRNA-122, a crucial biomarker used to assess the prognosis of gastric ulcers. This method combines the bridge catalytic hairpin assembly (bCHA)-based target sequence recycling with the primer exchange reaction (PER), resulting in a highly sensitive and label-free approach. Specifically, the bridge CHA technique, which offers superior target recognition accuracy and increased signal amplification efficiency compared to the classic CHA procedure, can selectively identify the target miRNA and release the complementary sequence to serve as a primer to facilitate the PER. This PER process produces a large number of G-quadruplex sequences, which then bind with thioflavin T to significantly increase its fluorescence. This enhanced fluorescence is used to detect miRNA-122, with a detection limit as low as 3.12 fM. The proposed approach can achieve exact discrimination of the target miRNA-122. Due to its label-free character, high selectivity, and sensitivity, this technology can serve as a practical and universal approach for detecting different biomarkers in the early stages of gastrointestinal diseases.

{"title":"Sensitive and reliable gastric ulcer related MicroRNA detection by bridge catalytic hairpin assembly (bCHA) mediated primer exchange reaction","authors":"Ligong Wang , Shan Zhao , Pang Hui , Kaige Zhang","doi":"10.1016/j.bmcl.2025.130153","DOIUrl":"10.1016/j.bmcl.2025.130153","url":null,"abstract":"<div><div>MicroRNAs (miRNA) have a significant role in the progression of gastric ulcer, and the sensitive and reliable detection of miRNAs is pivotal for the early diagnosis and treatment of gastrointestinal diseases. In this study, we developed a novel and efficient method for detecting miRNA-122, a crucial biomarker used to assess the prognosis of gastric ulcers. This method combines the bridge catalytic hairpin assembly (bCHA)-based target sequence recycling with the primer exchange reaction (PER), resulting in a highly sensitive and label-free approach. Specifically, the bridge CHA technique, which offers superior target recognition accuracy and increased signal amplification efficiency compared to the classic CHA procedure, can selectively identify the target miRNA and release the complementary sequence to serve as a primer to facilitate the PER. This PER process produces a large number of G-quadruplex sequences, which then bind with thioflavin T to significantly increase its fluorescence. This enhanced fluorescence is used to detect miRNA-122, with a detection limit as low as 3.12 fM. The proposed approach can achieve exact discrimination of the target miRNA-122. Due to its label-free character, high selectivity, and sensitivity, this technology can serve as a practical and universal approach for detecting different biomarkers in the early stages of gastrointestinal diseases.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"121 ","pages":"Article 130153"},"PeriodicalIF":2.5,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A review-plant medicine and its extraction components inhibit influenza virus

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-02-21 DOI: 10.1016/j.bmcl.2025.130151

Jiejie Lu , Zhenzhen Liu , Ziyan Li , Jiahui Su , Haojie Zhen , Ying Qu , Piet Herdewijn , Hongmin Liu , Ying Liu , Zhenya Wang

Influenza is a highly prevalent and highly contagious lung disease caused by influenza viruses. The main anti-influenza strategies are vaccination and antiviral drugs. Vaccination is an effective means of prevention, but the time lag in research and development makes it difficult to respond immediately to an outbreak. Approved drugs are mainly inhibitors of neuraminidase and M2 ion channels, but, due to the variability of influenza viruses, resistance to these drugs may emerge. Botanicals and their extracts have shown unique advantages in influenza treatment and are widely used in clinics across China. However, there are few reviews on the prevention and treatment of influenza with herbal medicines. We undertook a review of relevant literature in recent years to analyze the research progress of various botanicals and their extracts in the prevention and treatment of influenza. Our review provides theoretical support for the prevention and treatment of influenza by plant-based medicines, as well as new ideas for the development of novel low-toxicity and multi-target drugs.

{"title":"A review-plant medicine and its extraction components inhibit influenza virus","authors":"Jiejie Lu , Zhenzhen Liu , Ziyan Li , Jiahui Su , Haojie Zhen , Ying Qu , Piet Herdewijn , Hongmin Liu , Ying Liu , Zhenya Wang","doi":"10.1016/j.bmcl.2025.130151","DOIUrl":"10.1016/j.bmcl.2025.130151","url":null,"abstract":"<div><div>Influenza is a highly prevalent and highly contagious lung disease caused by influenza viruses. The main anti-influenza strategies are vaccination and antiviral drugs. Vaccination is an effective means of prevention, but the time lag in research and development makes it difficult to respond immediately to an outbreak. Approved drugs are mainly inhibitors of neuraminidase and M2 ion channels, but, due to the variability of influenza viruses, resistance to these drugs may emerge. Botanicals and their extracts have shown unique advantages in influenza treatment and are widely used in clinics across China. However, there are few reviews on the prevention and treatment of influenza with herbal medicines. We undertook a review of relevant literature in recent years to analyze the research progress of various botanicals and their extracts in the prevention and treatment of influenza. Our review provides theoretical support for the prevention and treatment of influenza by plant-based medicines, as well as new ideas for the development of novel low-toxicity and multi-target drugs.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130151"},"PeriodicalIF":2.5,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Oligonucleotide-based telomerase inhibitors with a photoresponsive α-chloroaldehyde

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-02-20 DOI: 10.1016/j.bmcl.2025.130138

Kentaro Kobata, Kazuki Matsubara, Risa Nishikawa, Yuki Narita, Kazuya Matsuo, Tomonori Waku, Akio Kobori

Telomerase, a ribonucleoprotein, is a reverse transcriptase that uses telomerase RNA component (hTR) as a template to elongate telomeric DNA at the ends of chromosomes. This enzyme plays a critical role in oncogenic cellular transformation. Therefore, the telomerase is considered an attractive target for cancer therapy. In this study, we synthesized photo-cross-linking oligodeoxyribonucleotides (ODNs) with a photoresponsive α-chloroaldehyde (PCA) moiety at the 3′-end or the 5′-end of the ODNs and evaluated the inhibition efficiencies for telomerase activity. PCA-modified ODNs with a sequence complementary to the template RNA of telomerase inhibited telomerase activity upon UV irradiation, whereas those with scramble sequence showed no significant inhibition. The 50 % inhibitory concentration (IC₅₀) of PCA-modified ODN was significantly reduced by UV irradiation. These results indicate that PCA-modified ODN inhibits telomerase activity in a sequence-selective manner and that the inhibitory activity is enhanced by the cross-linking reaction following UV irradiation.

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