The escalating threat of Methicillin-resistant Staphylococcus aureus (MRSA) infections seriously endangers human health, so facing the immense threat of drug-resistant bacteria, discovering new and potent antibacterial drugs less prone to inducing resistance is urgently needed. In this study, four amphiphilic ruthenium polypyridyl complexes were synthesized, namely [Ru(II)(bpy)2(DIPPB)] (PF6)3 (Ru-1), [Ru(II)(dmb)2(DIPPB)] (PF6)3 (Ru-2), [Ru(II)(dmob)2(DIPPB)] (PF6)3 (Ru-3) and [Ru(II)(bpy)2(DIPPB)] (PF6)3 (Ru-4). Among these complexes, complex Ru-4 incorporates N-methylimidazole and quaternary ammonium cations, in vitro experiments have demonstrated the presence of potent antibacterial activity against Staphylococcus aureus and MRSA, accompanied by low hemolytic activity and a diminished tendency to induce drug resistance. It acts by disrupting bacterial membranes via interaction with phosphatidylglycerol and phosphatidylethanolamine, increasing permeability, elevating ROS levels, and causing content leakage. Transcriptomics confirmed its impact on membrane-related genes. Notably, in vivo experimental results demonstrated that Ru-4 exhibits superior efficacy compared to vancomycin, thereby identifying it as a promising therapeutic candidate for MRSA infection treatment.
{"title":"Design and Synthesis of Membrane-Targeting Poly-Ruthenium Complexes Containing Quaternary Ammonium Cations with Potential Antibacterial Activity against Methicillin-Resistant Staphylococcus aureus (MRSA)","authors":"Runyu Xue,Cunhong Luo,Lixin Dou,Xinru Yu,Liao Xiangwen,Wang Jintao,Rujian Yu,Yanshi Xiong","doi":"10.1021/acs.jmedchem.5c02644","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02644","url":null,"abstract":"The escalating threat of Methicillin-resistant Staphylococcus aureus (MRSA) infections seriously endangers human health, so facing the immense threat of drug-resistant bacteria, discovering new and potent antibacterial drugs less prone to inducing resistance is urgently needed. In this study, four amphiphilic ruthenium polypyridyl complexes were synthesized, namely [Ru(II)(bpy)2(DIPPB)] (PF6)3 (Ru-1), [Ru(II)(dmb)2(DIPPB)] (PF6)3 (Ru-2), [Ru(II)(dmob)2(DIPPB)] (PF6)3 (Ru-3) and [Ru(II)(bpy)2(DIPPB)] (PF6)3 (Ru-4). Among these complexes, complex Ru-4 incorporates N-methylimidazole and quaternary ammonium cations, in vitro experiments have demonstrated the presence of potent antibacterial activity against Staphylococcus aureus and MRSA, accompanied by low hemolytic activity and a diminished tendency to induce drug resistance. It acts by disrupting bacterial membranes via interaction with phosphatidylglycerol and phosphatidylethanolamine, increasing permeability, elevating ROS levels, and causing content leakage. Transcriptomics confirmed its impact on membrane-related genes. Notably, in vivo experimental results demonstrated that Ru-4 exhibits superior efficacy compared to vancomycin, thereby identifying it as a promising therapeutic candidate for MRSA infection treatment.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"159 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-04DOI: 10.1021/acs.jmedchem.5c03845
Nan Zheng, Longfang Tu, Pu Xu, Rongfang Chen, Jiang Lu, Wan Dai, Yanxia Lin, Jianmei Ouyang, Jinying Qiu, You Wang, Leiming Wang, Weijun Shen
Harnessing the simultaneous activation of GLP-1R, GIPR, and GCGR has emerged as a highly promising therapeutic paradigm for obesity and related metabolic diseases, including nonalcoholic steatohepatitis (NASH). Here, we report the discovery of TPM003, a novel unimolecular GLP-1R/GIPR/GCGR triple agonist engineered by using a long-acting PEG-fatty acid (PEG-FA) stapling technology. TPM003 exhibits balanced triple receptor agonism and demonstrates an extended systemic half-life across multiple species. In obese mice, TPM003 induced robust and durable weight loss, accompanied by broad improvements in metabolic parameters, outperforming current GLP-1RA standards. Importantly, TPM003 also effectively reversed hepatic steatosis and improved markers of liver function in multiple NASH models. Furthermore, TPM003 is compatible with SNAC-based absorption enhancement, enabling oral delivery in a tablet formulation. Collectively, these findings highlight the therapeutic advantages of balanced GLP-1R/GIPR/GCGR agonism for obesity and NASH and support TPM003 as a promising preclinical candidate with translational potential.
{"title":"Discovery and Preclinical Evaluation of TPM003: A Novel GLP-1/GIP/Glucagon Triple Hormone Receptor Agonist with Robust Efficacy in Obesity and NASH","authors":"Nan Zheng, Longfang Tu, Pu Xu, Rongfang Chen, Jiang Lu, Wan Dai, Yanxia Lin, Jianmei Ouyang, Jinying Qiu, You Wang, Leiming Wang, Weijun Shen","doi":"10.1021/acs.jmedchem.5c03845","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03845","url":null,"abstract":"Harnessing the simultaneous activation of GLP-1R, GIPR, and GCGR has emerged as a highly promising therapeutic paradigm for obesity and related metabolic diseases, including nonalcoholic steatohepatitis (NASH). Here, we report the discovery of TPM003, a novel unimolecular GLP-1R/GIPR/GCGR triple agonist engineered by using a long-acting PEG-fatty acid (PEG-FA) stapling technology. TPM003 exhibits balanced triple receptor agonism and demonstrates an extended systemic half-life across multiple species. In obese mice, TPM003 induced robust and durable weight loss, accompanied by broad improvements in metabolic parameters, outperforming current GLP-1RA standards. Importantly, TPM003 also effectively reversed hepatic steatosis and improved markers of liver function in multiple NASH models. Furthermore, TPM003 is compatible with SNAC-based absorption enhancement, enabling oral delivery in a tablet formulation. Collectively, these findings highlight the therapeutic advantages of balanced GLP-1R/GIPR/GCGR agonism for obesity and NASH and support TPM003 as a promising preclinical candidate with translational potential.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"31 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146116010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-03DOI: 10.1021/acs.jmedchem.5c02427
Vid Kavaš, Carlos Contreras-Martel, Stane Pajk, Damijan Knez, Alexandre Martins, Thomas A. Gould, David I. Roper, Irena Zdovc, Andréa Dessen, Martina Hrast Rambaher, Stanislav Gobec
Monobactams, a subclass of β-lactam antibiotics with a monocyclic scaffold, are uniquely resistant to hydrolysis by metallo-β-lactamases, providing a distinct therapeutic advantage. Here, we report an in silico-based structure–activity relationship (SAR) investigation of aztreonam-related monobactams. A focused library of monobactam derivatives was synthesized and evaluated for inhibition of penicillin-binding proteins (PBPs) and antibacterial activity. Ten compounds, including aztreonam, were crystallized with truncated PBP1b from Streptococcus pneumoniae, used as a model PBP. Potent PBP1b inhibitors were developed, although high enzymatic potency was not always reflected in strong antibacterial activity. Certain derivatives showed activity against Staphylococcus aureus, which is typically resistant to monobactams. 2D similarity search identified potent inhibitors active against Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. Crystal structures revealed previously unrecognized binding interactions, including a halogen bond with a conserved threonine residue, underscoring the potential of these interactions to support the development of more potent PBP inhibitors.
{"title":"Structure–Activity Relationship and Crystallographic Study of New Monobactams","authors":"Vid Kavaš, Carlos Contreras-Martel, Stane Pajk, Damijan Knez, Alexandre Martins, Thomas A. Gould, David I. Roper, Irena Zdovc, Andréa Dessen, Martina Hrast Rambaher, Stanislav Gobec","doi":"10.1021/acs.jmedchem.5c02427","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02427","url":null,"abstract":"Monobactams, a subclass of β-lactam antibiotics with a monocyclic scaffold, are uniquely resistant to hydrolysis by metallo-β-lactamases, providing a distinct therapeutic advantage. Here, we report an <i>in silico</i>-based structure–activity relationship (SAR) investigation of aztreonam-related monobactams. A focused library of monobactam derivatives was synthesized and evaluated for inhibition of penicillin-binding proteins (PBPs) and antibacterial activity. Ten compounds, including aztreonam, were crystallized with truncated PBP1b from <i>Streptococcus pneumoniae</i>, used as a model PBP. Potent PBP1b inhibitors were developed, although high enzymatic potency was not always reflected in strong antibacterial activity. Certain derivatives showed activity against <i>Staphylococcus aureus</i>, which is typically resistant to monobactams. 2D similarity search identified potent inhibitors active against <i>Escherichia coli</i>, <i>Klebsiella pneumoniae</i>, and <i>Acinetobacter baumannii</i>. Crystal structures revealed previously unrecognized binding interactions, including a halogen bond with a conserved threonine residue, underscoring the potential of these interactions to support the development of more potent PBP inhibitors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"23 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Simultaneous optimization of tumor accumulation and photothermal conversion efficiency (PCE) remains a major challenge in photothermal agent (PTA) development. Here, benzene-thiol/-dithio/-trithiol was introduced at the meso-position of heptamethine cyanine (Cy7) via sulfhydryl substitution. The obtained derivatives, denoted as M-Cy7, D-Cy7, and T-Cy7, conferred enhanced molecular flexibility, promoting self-assembly and passive tumor accumulation. Although increasing the number of Cy7 units reduced molecular flexibility in the D- and T-derivatives, the central phenyl linker enabled covalent coupling of intramolecular Cy7 moieties, resulting in a “covalent aggregation” effect and boosting PCE to 77%─nearly seven times higher than that of the prototypic Cy7. Among them, D-Cy7 demonstrated the most favorable balance of tumor accumulation and photothermal efficiency, achieving optimal in vivo PTT efficacy. This novel molecular design strategy successfully integrated high PCE and tumor-targeting capability into a single PTA, offering new insights for advancing photothermal therapy.
{"title":"Flexible-Structured Cyanine–Cyanine Conjugate Affords Highly Efficient Photothermal Therapy via Enhanced Tumor Accumulation and Heating Performance","authors":"Yanxian Hou,Yinhao Lin,Linying Wang,Yongshuai Kang,Songyang Lin,Yuqi Han,Youting Zhang,Qing Yao,Ruijie Chen,Longfa Kou","doi":"10.1021/acs.jmedchem.5c03584","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03584","url":null,"abstract":"Simultaneous optimization of tumor accumulation and photothermal conversion efficiency (PCE) remains a major challenge in photothermal agent (PTA) development. Here, benzene-thiol/-dithio/-trithiol was introduced at the meso-position of heptamethine cyanine (Cy7) via sulfhydryl substitution. The obtained derivatives, denoted as M-Cy7, D-Cy7, and T-Cy7, conferred enhanced molecular flexibility, promoting self-assembly and passive tumor accumulation. Although increasing the number of Cy7 units reduced molecular flexibility in the D- and T-derivatives, the central phenyl linker enabled covalent coupling of intramolecular Cy7 moieties, resulting in a “covalent aggregation” effect and boosting PCE to 77%─nearly seven times higher than that of the prototypic Cy7. Among them, D-Cy7 demonstrated the most favorable balance of tumor accumulation and photothermal efficiency, achieving optimal in vivo PTT efficacy. This novel molecular design strategy successfully integrated high PCE and tumor-targeting capability into a single PTA, offering new insights for advancing photothermal therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"17 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-03DOI: 10.1021/acs.jmedchem.5c03477
Zhiqiong Luo, Guangcan Xu, Cheng Li, Zhilu Sun, Haonan Chen, Mingyue Yang, Yi Ye, Qianyu Chen, Bixue Xu, Heng Luo, Baofei Sun
Cystathionine γ-lyase (CTH) is markedly enriched in glioblastoma (GBM) and is associated with poor patient survival, enhanced temozolomide (TMZ) resistance, and aggressive phenotypes; however, effective CTH inhibitors for GBM therapy are currently lacking. Using click chemistry-based target identification, we identified cystathionine γ-lyase (CTH) as the direct molecular target of a novel 4-trifluoromethylquinoline derivative, TKL002. TKL002 exhibits strong antitumor activity both in vitro and in vivo, inducing late-stage apoptosis and G2/M cell cycle arrest. Mechanistically, TKL002 inhibits CTH activity, reduces hydrogen sulfide (H2S) production, suppresses NF-κB phosphorylation, and downregulates pro-inflammatory cytokine expression. In addition, TKL002 inhibits GBM cell migration and invasion by upregulating E-cadherin and downregulating N-cadherin and vimentin. Collectively, these findings demonstrate that TKL002 exerts potent antiglioblastoma activity via modulation of the CTH/H2S/NF-κB/EMT signaling axis, highlighting its potential as a quinoline-based therapeutic candidate to overcome intrinsic GBM resistance and invasiveness.
{"title":"Hijacking the Hydrogen Sulfide Axis: A Novel 4-Trifluoromethylquinoline Derivative Suppresses Glioblastoma via Cystathionine γ-Lyase Suppression","authors":"Zhiqiong Luo, Guangcan Xu, Cheng Li, Zhilu Sun, Haonan Chen, Mingyue Yang, Yi Ye, Qianyu Chen, Bixue Xu, Heng Luo, Baofei Sun","doi":"10.1021/acs.jmedchem.5c03477","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03477","url":null,"abstract":"Cystathionine γ-lyase (CTH) is markedly enriched in glioblastoma (GBM) and is associated with poor patient survival, enhanced temozolomide (TMZ) resistance, and aggressive phenotypes; however, effective CTH inhibitors for GBM therapy are currently lacking. Using click chemistry-based target identification, we identified cystathionine γ-lyase (CTH) as the direct molecular target of a novel 4-trifluoromethylquinoline derivative, <b>TKL002</b>. <b>TKL002</b> exhibits strong antitumor activity both in vitro and in vivo, inducing late-stage apoptosis and G<sub>2</sub>/M cell cycle arrest. Mechanistically, <b>TKL002</b> inhibits CTH activity, reduces hydrogen sulfide (H<sub>2</sub>S) production, suppresses NF-κB phosphorylation, and downregulates pro-inflammatory cytokine expression. In addition, <b>TKL002</b> inhibits GBM cell migration and invasion by upregulating E-cadherin and downregulating N-cadherin and vimentin. Collectively, these findings demonstrate that <b>TKL002</b> exerts potent antiglioblastoma activity via modulation of the CTH/H<sub>2</sub>S/NF-κB/EMT signaling axis, highlighting its potential as a quinoline-based therapeutic candidate to overcome intrinsic GBM resistance and invasiveness.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"90 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer chemoimmunotherapy based on metal complexes has attracted wide interest for its ability to eliminate tumor cells while activating antitumor immunity, primarily by inducing immunogenic cell death (ICD). However, clinical translation of ICD inducers remains challenging, underscoring the need for inducers that elicit ICD via alternative cell death mechanisms. Necroptosis represents a potent yet underutilized route to trigger ICD. Herein, we designed a series of stable Au(III) complexes incorporating an isoquinoline-derived cyclometalated C^N ligand and various strong electron-donating S^S or N^N auxiliary ligands. Among them, Au-1 exhibited potent cytotoxicity, inhibited thioredoxin reductase (TrxR), elevated intracellular ROS, and triggered ROS-mediated necroptosis. This process elicited robust necroptosis-dependent ICD. In vivo, Au-1 significantly suppressed tumor growth, remodeled the tumor immune microenvironment, and synergized effectively with anti-PD-1 therapy. This work presents the first rationally designed cyclometalated Au(III) complex that functions as a necroptosis-dependent ICD inducer, offering a promising strategy for metal-based chemoimmunotherapy.
{"title":"Stable Cyclometalated Gold(III) Complex Engaging Isoquinoline Derivative and Disulfur Ligand Elicits Necroptosis-Dependent Immunogenic Cell Death","authors":"Wei Zhang,Liang-Mei Yang,Yi Zhao,Meng-Ya Li,Ya-Qian Shi,Yuan Lu,Xu-Sheng Wang,Song He,Feng-Yang Wang,Ke-Bin Huang,Hong Liang","doi":"10.1021/acs.jmedchem.5c03654","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03654","url":null,"abstract":"Cancer chemoimmunotherapy based on metal complexes has attracted wide interest for its ability to eliminate tumor cells while activating antitumor immunity, primarily by inducing immunogenic cell death (ICD). However, clinical translation of ICD inducers remains challenging, underscoring the need for inducers that elicit ICD via alternative cell death mechanisms. Necroptosis represents a potent yet underutilized route to trigger ICD. Herein, we designed a series of stable Au(III) complexes incorporating an isoquinoline-derived cyclometalated C^N ligand and various strong electron-donating S^S or N^N auxiliary ligands. Among them, Au-1 exhibited potent cytotoxicity, inhibited thioredoxin reductase (TrxR), elevated intracellular ROS, and triggered ROS-mediated necroptosis. This process elicited robust necroptosis-dependent ICD. In vivo, Au-1 significantly suppressed tumor growth, remodeled the tumor immune microenvironment, and synergized effectively with anti-PD-1 therapy. This work presents the first rationally designed cyclometalated Au(III) complex that functions as a necroptosis-dependent ICD inducer, offering a promising strategy for metal-based chemoimmunotherapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"9 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Compared with positive control MRTX849, the synthesized compounds 7g, 7p, 7q, 7r, 7v, and 7y displayed stronger antiproliferative activities against H358 cells with IC50 values of < 1 nM (3D cell culture) and comparable inhibitory potency against KRASG12C. Among them, 7q (MH5) exhibited satisfactory cellular selectivity, moderate pharmacokinetic characters, and good anticancer effects on pancreatic, colorectal cancer xenograft in vivo. Meaningfully, 7q combined with Nrf2 inhibitor ML385 or PARP7 inhibitor RBN-2397 greatly enhanced the sensitivity of 7q against lung cells (H1373) in vivo. Furthermore, combination therapy of 7q with pan-USP inhibitor PR-619 obtained a statistically significant synergistic inhibition of H1373 cell growth in vitro and in vivo. Our findings indicate that 7q may be a promising drug candidate for the treatment of cancers harboring the KRASG12C mutation, and the results of the combination regimen established a pharmacological foundation for addressing drug resistance.
{"title":"Design and Synthesis of KRASG12C Inhibitors for Antitumor Evaluation Harboring Combination Therapy with Nrf2, PARP-7, and Pan-USP Inhibitors to Alleviate Drug Resistance Synergistically","authors":"Liangliang Tian,Qingxuan Han,Yanlong Qiao,Peng Chu,Lixue Chen","doi":"10.1021/acs.jmedchem.5c02703","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02703","url":null,"abstract":"Compared with positive control MRTX849, the synthesized compounds 7g, 7p, 7q, 7r, 7v, and 7y displayed stronger antiproliferative activities against H358 cells with IC50 values of < 1 nM (3D cell culture) and comparable inhibitory potency against KRASG12C. Among them, 7q (MH5) exhibited satisfactory cellular selectivity, moderate pharmacokinetic characters, and good anticancer effects on pancreatic, colorectal cancer xenograft in vivo. Meaningfully, 7q combined with Nrf2 inhibitor ML385 or PARP7 inhibitor RBN-2397 greatly enhanced the sensitivity of 7q against lung cells (H1373) in vivo. Furthermore, combination therapy of 7q with pan-USP inhibitor PR-619 obtained a statistically significant synergistic inhibition of H1373 cell growth in vitro and in vivo. Our findings indicate that 7q may be a promising drug candidate for the treatment of cancers harboring the KRASG12C mutation, and the results of the combination regimen established a pharmacological foundation for addressing drug resistance.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"295 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Targeting the interaction between the C-terminal domain of the GluA2 subunit of AMPA receptors and BRAG2 presents a highly promising therapeutic approach for acute ischemic stroke. The membrane-permeable peptide Tat-GluA2-3Y has shown potential by competitively binding to BRAG2 to inhibit GluA2 endocytosis; however, its clinical application is limited due to poor stability in vivo. To address this limitation, we developed stapled peptides based on GluA2-3Y, leading to the identification of the lead compound P3LC7LC-P, which exhibits high-affinity binding to BRAG2. Functionally, P3LC7LC-P offers strong neuroprotection in two injury models: oxygen–glucose deprivation-induced and glutamate-induced neurotoxicity. Notably, P3LC7LC-P significantly improved plasma stability compared to Tat-GluA2-3Y, with a half-life exceeding 372.7 min. In the transient middle cerebral artery occlusion (tMCAO) model, P3LC7LC-P reduced cerebral infarction areas to 21.00% at a dose of 8 mg/kg. These findings highlight P3LC7LC-P as a promising candidate for the development of novel therapies for ischemic stroke.
{"title":"Stapled Peptides with Therapeutic Potential for Ischemic Stroke by Blocking the Endocytosis of GluA2 AMPAR","authors":"Yujiao Qin,Qingye Zhu,Zhixiang Yan,Xin Chen,Jiacheng Wang,Xinru Zhang,Ruiguo Liang,Jiaying Han,Yi Mao,Xianglong Wang,Han Ju,Jie Zhou,Ping Li,Mingxin Dong","doi":"10.1021/acs.jmedchem.5c03140","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03140","url":null,"abstract":"Targeting the interaction between the C-terminal domain of the GluA2 subunit of AMPA receptors and BRAG2 presents a highly promising therapeutic approach for acute ischemic stroke. The membrane-permeable peptide Tat-GluA2-3Y has shown potential by competitively binding to BRAG2 to inhibit GluA2 endocytosis; however, its clinical application is limited due to poor stability in vivo. To address this limitation, we developed stapled peptides based on GluA2-3Y, leading to the identification of the lead compound P3LC7LC-P, which exhibits high-affinity binding to BRAG2. Functionally, P3LC7LC-P offers strong neuroprotection in two injury models: oxygen–glucose deprivation-induced and glutamate-induced neurotoxicity. Notably, P3LC7LC-P significantly improved plasma stability compared to Tat-GluA2-3Y, with a half-life exceeding 372.7 min. In the transient middle cerebral artery occlusion (tMCAO) model, P3LC7LC-P reduced cerebral infarction areas to 21.00% at a dose of 8 mg/kg. These findings highlight P3LC7LC-P as a promising candidate for the development of novel therapies for ischemic stroke.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"106 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-02DOI: 10.1021/acs.jmedchem.5c03704
Qiangqiang Wei,Ashley J. Taylor,Nagaraju Miriyala,Mahesh A. Barmade,Zachary O. Gentry,Jordan Anderson-Daniels,Kevin B. Teuscher,Mackenzie M. Crow,Chideraa Apakama,Taylor M. South,Tyson A. Rietz,Kangsa Amporndanai,Jason Phan,John L. Sensintaffar,Mark Denison,Taekyu Lee,Stephen W. Fesik
The papain-like protease (PLPro) plays a key role in SARS-CoV-2 replication and represents a promising target for the development of new antiviral therapies. Previous efforts to develop fragment-derived inhibitors of PLPro led to the identification of a novel class of spiro[chromane-2,4′-piperidin]-4-one inhibitors exemplified by lead compound 7. High-resolution covalent cocrystal structures and molecular dynamics simulations were utilized to guide the development of a series of low-nanomolar irreversible PLPro inhibitors, with lead compound 45 demonstrating strong enzymatic inhibition (IC50 = 0.059 μM at T = 60 min) and antiviral activity in A549 cells (EC50 = 2.1 μM at 48 hpi). This novel class of inhibitors represents a promising avenue for the development of therapeutics to overcome the potential of drug-resistant viral strains and future coronavirus outbreaks.
{"title":"Discovery of Spiro[chromane-2,4′-piperidine] Derivatives as Irreversible Inhibitors of SARS-CoV-2 Papain-like Protease","authors":"Qiangqiang Wei,Ashley J. Taylor,Nagaraju Miriyala,Mahesh A. Barmade,Zachary O. Gentry,Jordan Anderson-Daniels,Kevin B. Teuscher,Mackenzie M. Crow,Chideraa Apakama,Taylor M. South,Tyson A. Rietz,Kangsa Amporndanai,Jason Phan,John L. Sensintaffar,Mark Denison,Taekyu Lee,Stephen W. Fesik","doi":"10.1021/acs.jmedchem.5c03704","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03704","url":null,"abstract":"The papain-like protease (PLPro) plays a key role in SARS-CoV-2 replication and represents a promising target for the development of new antiviral therapies. Previous efforts to develop fragment-derived inhibitors of PLPro led to the identification of a novel class of spiro[chromane-2,4′-piperidin]-4-one inhibitors exemplified by lead compound 7. High-resolution covalent cocrystal structures and molecular dynamics simulations were utilized to guide the development of a series of low-nanomolar irreversible PLPro inhibitors, with lead compound 45 demonstrating strong enzymatic inhibition (IC50 = 0.059 μM at T = 60 min) and antiviral activity in A549 cells (EC50 = 2.1 μM at 48 hpi). This novel class of inhibitors represents a promising avenue for the development of therapeutics to overcome the potential of drug-resistant viral strains and future coronavirus outbreaks.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"92 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-02DOI: 10.1021/acs.jmedchem.5c03568
Anas Ansari, Radoslaw T. Chrzanowski, Huiying Li, Christine D. Hardy, Amardeep Awasthi, Thomas L. Poulos, Richard B. Silverman
Neuronal nitric oxide synthase (nNOS) is a therapeutic target for the treatment of various neurological disorders and for melanoma. As part of our ongoing efforts to develop potent and selective nNOS inhibitors, we modified our previously reported compound 3 to 4 by introducing an ether linker, leading to a new series of ether-linked 2-aminopyridine-based compounds that exhibit high potency, isoform selectivity, and membrane permeability. Among them, lead compound 4 inhibits human nNOS with a Ki of 25 nM and exhibits 2300-fold selectivity over human endothelial NOS (eNOS) while also displaying high effective permeability in the parallel artificial membrane permeability assay for the blood–brain barrier (PAMPA-BBB) assay (Pe = 16.67 × 10–6 cm/s), indicating favorable blood–brain barrier penetration. Pharmacokinetic evaluation confirmed the brain penetrance of 4 and demonstrated a high oral bioavailability (77%). Moreover, the X-ray crystal structures of representative compounds bound to three NOS isoforms (hnNOS, rnNOS, and heNOS) revealed key binding interactions that contribute to both potency and selectivity.
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