ACS Pharmacology and Translational Science最新文献

{"title":"Mechanistic Insights of a p53-Targeting Small Molecule","authors":"Ricardo J. F. Ferreira,&nbsp;Valentina Barcherini,&nbsp;Catarina Roma-Rodrigues,&nbsp;Miriama Sikorová,&nbsp;Lucília Saraiva,&nbsp;Ana P. Leandro,&nbsp;Pedro V. Baptista,&nbsp;Alexandra R. Fernandes,&nbsp;Alexandra M. M. Antunes* and Maria M. M. Santos*,&nbsp;","doi":"10.1021/acsptsci.5c0011010.1021/acsptsci.5c00110","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00110https://doi.org/10.1021/acsptsci.5c00110","url":null,"abstract":"<p >Restoring the p53 pathway, particularly by reactivating wild-type (wt) or mutant (mut) p53, is considered a promising approach for cancer treatment. Previously, we identified the tryptophanol-derived oxazoloisoindolinone family as a new scaffold for obtaining wt and mut p53 reactivators. Herein, we report a detailed study on the pharmacokinetic profile and the mechanism of action of <b>RVJB59</b>, an (<i>R</i>)-tryptophanol-derived oxazoloisoindolinone that exhibits six times higher activity and increased selectivity for HCT116 cells with p53 compared to our initial hit, <b>SLMP53–1</b>. <i>In vitro</i> metabolic degradation studies in human liver microsomes and rat liver S9 fractions, assessed by LC/HRMS/MS, showed that <b>RVJB59</b> is a low-clearance compound. The three main metabolites identified were synthesized, and their antiproliferative activity was evaluated against HCT116 colon cancer cells with and without p53, showing a loss of activity when compared to <b>RVJB59</b>. DSF studies showed that <b>RVJB59</b> enhances the thermostability of the wt and R273H p53 DNA-binding domain, with this mutant showing melting curves with two melting transitions, distinct from those obtained for the wild-type. The ability of <b>RVJB59</b> to undergo covalent binding via nucleophilic aromatic substitution was assessed by HRMS/MS, using glutathione and wt p53 as case studies. These assays showed low reactivity toward glutathione and remarkable selectivity toward Cys141 of wt p53. The effect of <b>RVJB59</b> was also evaluated in 3D spheroids of HCT116 cells and <i>in vivo</i> using chicken embryos, with <b>RVJB59</b> reducing 3D tumor spheroid growth and exhibiting antiangiogenic potential. This study provides additional evidence of the potential of <b>RVJB59</b> in activating p53.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1726–1740 1726–1740"},"PeriodicalIF":4.9,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic Insights of a p53-Targeting Small Molecule.","authors":"Ricardo J F Ferreira, Valentina Barcherini, Catarina Roma-Rodrigues, Miriama Sikorová, Lucília Saraiva, Ana P Leandro, Pedro V Baptista, Alexandra R Fernandes, Alexandra M M Antunes, Maria M M Santos","doi":"10.1021/acsptsci.5c00110","DOIUrl":"10.1021/acsptsci.5c00110","url":null,"abstract":"<p><p>Restoring the p53 pathway, particularly by reactivating wild-type (wt) or mutant (mut) p53, is considered a promising approach for cancer treatment. Previously, we identified the tryptophanol-derived oxazoloisoindolinone family as a new scaffold for obtaining wt and mut p53 reactivators. Herein, we report a detailed study on the pharmacokinetic profile and the mechanism of action of <b>RVJB59</b>, an (<i>R</i>)-tryptophanol-derived oxazoloisoindolinone that exhibits six times higher activity and increased selectivity for HCT116 cells with p53 compared to our initial hit, <b>SLMP53-1</b>. <i>In vitro</i> metabolic degradation studies in human liver microsomes and rat liver S9 fractions, assessed by LC/HRMS/MS, showed that <b>RVJB59</b> is a low-clearance compound. The three main metabolites identified were synthesized, and their antiproliferative activity was evaluated against HCT116 colon cancer cells with and without p53, showing a loss of activity when compared to <b>RVJB59</b>. DSF studies showed that <b>RVJB59</b> enhances the thermostability of the wt and R273H p53 DNA-binding domain, with this mutant showing melting curves with two melting transitions, distinct from those obtained for the wild-type. The ability of <b>RVJB59</b> to undergo covalent binding via nucleophilic aromatic substitution was assessed by HRMS/MS, using glutathione and wt p53 as case studies. These assays showed low reactivity toward glutathione and remarkable selectivity toward Cys141 of wt p53. The effect of <b>RVJB59</b> was also evaluated in 3D spheroids of HCT116 cells and <i>in vivo</i> using chicken embryos, with <b>RVJB59</b> reducing 3D tumor spheroid growth and exhibiting antiangiogenic potential. This study provides additional evidence of the potential of <b>RVJB59</b> in activating p53.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1726-1740"},"PeriodicalIF":4.9,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Neutrophil-Mediated Inflammation: Identification of Pyrazolidinone Carboxamide Derivatives as Potent Selective Inhibitors of Formyl Peptide Receptor 1 (FPR1)-Activated Neutrophils","authors":"Mohammad Abdel-Halim*,&nbsp;Reem A. Wagdy,&nbsp;Mohamed Salah,&nbsp;Yi-Hsuan Wang,&nbsp;Tzu-Peng Cheng,&nbsp;Yao-Rong Lee,&nbsp;Yu-Cheng Chen,&nbsp;Yasmine M. Mandour,&nbsp;Ashraf H. Abadi,&nbsp;Matthias Engel and Tsong-Long Hwang*,&nbsp;","doi":"10.1021/acsptsci.4c0071510.1021/acsptsci.4c00715","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00715https://doi.org/10.1021/acsptsci.4c00715","url":null,"abstract":"<p >Neutrophils play a critical role in the innate immune response, but their overactivation can lead to chronic inflammation and tissue damage in conditions such as rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and sepsis. Formyl peptide receptor 1 (FPR1) is a key regulator of neutrophil activation, making it an attractive target for therapeutic intervention. In this study, an in-house screening revealed pyrazolidinone carboxamide derivatives as effective inhibitors of neutrophil activation, exhibiting no cytotoxic effects. Compounds <b>10</b>–<b>12</b> and <b>21</b> demonstrated selective inhibition of FPR1-induced neutrophil superoxide anion production and elastase release with submicromolar IC₅₀ values, while having no effect on the FPR2 pathway. On a structural level, electron-withdrawing groups on the thiazole ring within the amide side chain were found to be crucial for high potency. Binding assays confirmed that compounds <b>10</b>, <b>11</b> and <b>21</b> act as direct antagonists of FPR1. In the LPS-induced acute respiratory distress syndrom (ARDS) model in mice, compound <b>10</b> significantly reduced pulmonary inflammation, oxidative stress, and neutrophil elastase activity, while showing no signs of toxicity in the liver or kidneys at the tested doses, highlighting its protective effects. Furthermore, molecular docking and dynamic simulations provided insights into their binding poses, explaining their interactions with key residues within the FPR1 binding site. This study lays the foundation for optimizing this class of compounds as therapeutic agents for controlling neutrophil-mediated inflammation.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1591–1609 1591–1609"},"PeriodicalIF":4.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights from Clinical Trials on A_2A Adenosine Receptor Antagonists for Cancer Treatment.","authors":"Pran Kishore Deb, Prasenjit Maity, Biprajit Sarkar, Katharigatta N Venugopala, Rakesh Kumar Tekade, Sanjay Batra","doi":"10.1021/acsptsci.5c00057","DOIUrl":"10.1021/acsptsci.5c00057","url":null,"abstract":"<p><p>Accumulation of high concentrations of adenosine (ADO) in the tumor microenvironment represents an important immunosuppressive mechanism that promotes cancer progression through A_2A receptor signaling. While initial clinical trials demonstrated modest anticancer effects of monotherapy with A_2A receptor antagonists, combination approaches, particularly with immune checkpoint inhibitors, have shown enhanced potential across multiple cancer types. This review examines the therapeutic potential of ADO/A_2A receptor modulation in bolstering antitumor immune responses, covering the intricate mechanisms of A_2A receptor signaling and ongoing clinical advancements of A_2A receptor antagonists and dual A_2A/A_2B receptor antagonists. Also, we discuss the pivotal role of rational combination strategies in restoring immunocompetence within the tumor microenvironment, thus offering promising prospects for overcoming immune evasion in cancer therapy.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1498-1512"},"PeriodicalIF":4.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights from Clinical Trials on A2A Adenosine Receptor Antagonists for Cancer Treatment","authors":"Pran Kishore Deb*,&nbsp;Prasenjit Maity,&nbsp;Biprajit Sarkar,&nbsp;Katharigatta N. Venugopala,&nbsp;Rakesh Kumar Tekade and Sanjay Batra,&nbsp;","doi":"10.1021/acsptsci.5c0005710.1021/acsptsci.5c00057","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00057https://doi.org/10.1021/acsptsci.5c00057","url":null,"abstract":"<p >Accumulation of high concentrations of adenosine (ADO) in the tumor microenvironment represents an important immunosuppressive mechanism that promotes cancer progression through A_2A receptor signaling. While initial clinical trials demonstrated modest anticancer effects of monotherapy with A_2A receptor antagonists, combination approaches, particularly with immune checkpoint inhibitors, have shown enhanced potential across multiple cancer types. This review examines the therapeutic potential of ADO/A_2A receptor modulation in bolstering antitumor immune responses, covering the intricate mechanisms of A_2A receptor signaling and ongoing clinical advancements of A_2A receptor antagonists and dual A_2A/A_2B receptor antagonists. Also, we discuss the pivotal role of rational combination strategies in restoring immunocompetence within the tumor microenvironment, thus offering promising prospects for overcoming immune evasion in cancer therapy.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1498–1512 1498–1512"},"PeriodicalIF":4.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Neutrophil-Mediated Inflammation: Identification of Pyrazolidinone Carboxamide Derivatives as Potent Selective Inhibitors of Formyl Peptide Receptor 1 (FPR1)-Activated Neutrophils.","authors":"Mohammad Abdel-Halim, Reem A Wagdy, Mohamed Salah, Yi-Hsuan Wang, Tzu-Peng Cheng, Yao-Rong Lee, Yu-Cheng Chen, Yasmine M Mandour, Ashraf H Abadi, Matthias Engel, Tsong-Long Hwang","doi":"10.1021/acsptsci.4c00715","DOIUrl":"10.1021/acsptsci.4c00715","url":null,"abstract":"<p><p>Neutrophils play a critical role in the innate immune response, but their overactivation can lead to chronic inflammation and tissue damage in conditions such as rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and sepsis. Formyl peptide receptor 1 (FPR1) is a key regulator of neutrophil activation, making it an attractive target for therapeutic intervention. In this study, an in-house screening revealed pyrazolidinone carboxamide derivatives as effective inhibitors of neutrophil activation, exhibiting no cytotoxic effects. Compounds <b>10</b>-<b>12</b> and <b>21</b> demonstrated selective inhibition of FPR1-induced neutrophil superoxide anion production and elastase release with submicromolar IC₅₀ values, while having no effect on the FPR2 pathway. On a structural level, electron-withdrawing groups on the thiazole ring within the amide side chain were found to be crucial for high potency. Binding assays confirmed that compounds <b>10</b>, <b>11</b> and <b>21</b> act as direct antagonists of FPR1. In the LPS-induced acute respiratory distress syndrom (ARDS) model in mice, compound <b>10</b> significantly reduced pulmonary inflammation, oxidative stress, and neutrophil elastase activity, while showing no signs of toxicity in the liver or kidneys at the tested doses, highlighting its protective effects. Furthermore, molecular docking and dynamic simulations provided insights into their binding poses, explaining their interactions with key residues within the FPR1 binding site. This study lays the foundation for optimizing this class of compounds as therapeutic agents for controlling neutrophil-mediated inflammation.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1591-1609"},"PeriodicalIF":4.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of Different Types of Cell Death by Noncoding RNAs: Molecular Insights and Therapeutic Implications","authors":"Reshmi Kumari,&nbsp; and ,&nbsp;Satarupa Banerjee*,&nbsp;","doi":"10.1021/acsptsci.4c0068110.1021/acsptsci.4c00681","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00681https://doi.org/10.1021/acsptsci.4c00681","url":null,"abstract":"<p >Noncoding RNAs (ncRNAs) are crucial regulatory molecules in various biological processes, despite not coding for proteins. ncRNAs are further divided into long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs) based on the size of their nucleotides. These ncRNAs play crucial roles in transcriptional, post-transcriptional, and epigenetic regulation. The regulatory roles of noncoding RNAs, including lncRNAs, miRNAs, and circRNAs, are essential in various modalities of cellular death, such as apoptosis, ferroptosis, cuproptosis, pyroptosis, disulfidptosis, and necroptosis. These noncoding RNAs are integral to modulating gene expression and protein functionality during cellular death mechanisms. In apoptosis, lncRNAs, miRNAs, and circRNAs influence the transcription of apoptotic genes. In ferroptosis, these noncoding RNAs target genes and proteins involved in iron homeostasis and oxidative stress responses. For cuproptosis, noncoding RNAs regulate pathways associated with the accumulation of copper ions, leading to cellular death. During pyroptosis, noncoding RNAs modulate inflammatory mediators and caspases, affecting the proinflammatory cell death pathway. In necroptosis, noncoding RNAs oversee the formation and functionality of necrosomes, thereby influencing the balance between cellular survival and death. Disulfidptosis is a unique type of regulated cell death caused by the excessive formation of disulfide bonds within cells, leading to cytoskeletal collapse and oxidative stress, especially under glucose-limited conditions. This investigation highlights the complex mechanisms through which noncoding RNAs coordinate cellular death, emphasizing their therapeutic promise as potential targets, particularly in the domain of cancer treatment.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"1205–1226 1205–1226"},"PeriodicalIF":4.9,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of Different Types of Cell Death by Noncoding RNAs: Molecular Insights and Therapeutic Implications.","authors":"Reshmi Kumari, Satarupa Banerjee","doi":"10.1021/acsptsci.4c00681","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00681","url":null,"abstract":"<p><p>Noncoding RNAs (ncRNAs) are crucial regulatory molecules in various biological processes, despite not coding for proteins. ncRNAs are further divided into long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs) based on the size of their nucleotides. These ncRNAs play crucial roles in transcriptional, post-transcriptional, and epigenetic regulation. The regulatory roles of noncoding RNAs, including lncRNAs, miRNAs, and circRNAs, are essential in various modalities of cellular death, such as apoptosis, ferroptosis, cuproptosis, pyroptosis, disulfidptosis, and necroptosis. These noncoding RNAs are integral to modulating gene expression and protein functionality during cellular death mechanisms. In apoptosis, lncRNAs, miRNAs, and circRNAs influence the transcription of apoptotic genes. In ferroptosis, these noncoding RNAs target genes and proteins involved in iron homeostasis and oxidative stress responses. For cuproptosis, noncoding RNAs regulate pathways associated with the accumulation of copper ions, leading to cellular death. During pyroptosis, noncoding RNAs modulate inflammatory mediators and caspases, affecting the proinflammatory cell death pathway. In necroptosis, noncoding RNAs oversee the formation and functionality of necrosomes, thereby influencing the balance between cellular survival and death. Disulfidptosis is a unique type of regulated cell death caused by the excessive formation of disulfide bonds within cells, leading to cytoskeletal collapse and oxidative stress, especially under glucose-limited conditions. This investigation highlights the complex mechanisms through which noncoding RNAs coordinate cellular death, emphasizing their therapeutic promise as potential targets, particularly in the domain of cancer treatment.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"1205-1226"},"PeriodicalIF":4.9,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficient Small-Molecule Reversal Agents for Anticoagulant Fondaparinux","authors":"Daniel Carbajo,&nbsp;Yolanda Pérez,&nbsp;Gabriela F. Castelo,&nbsp;Eva Prats,&nbsp;Jordi Bujons and Ignacio Alfonso*,&nbsp;","doi":"10.1021/acsptsci.4c0074710.1021/acsptsci.4c00747","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00747https://doi.org/10.1021/acsptsci.4c00747","url":null,"abstract":"<p >Fondaparinux is a highly anionic synthetic heparinoid pentasaccharide used as an anticoagulant for specific clinical conditions and surgeries. As a non-natural small-molecule drug, it presents pharmacokinetic and pharmacodynamic advantages, as well as high stability and low immunogenicity, when compared with different forms of heparin. However, its broader usage is hampered by different factors like price, existence of alternative anticoagulants, or, specifically in this case, the lack of an effective antidote that is highly recommendable for avoiding uncontrolled bleeding. In this work, we describe two synthetic small molecules derived from spermine (3AC and 3FF) that efficiently revert the anticoagulant activity of fondaparinux. In an <i>in vitro</i> enzymatic assay related to blood coagulation, the spermine derivatives show potent activity as fondaparinux antidotes, with higher activity than ciraparantag (a small molecule in the clinical phase as an anticoagulant antidote) and much higher activity than protamine, the only approved antidote for unfractioned heparin but inefficient against fondaparinux. Remarkably, naked-eye <i>ex vivo</i> tests demonstrated their efficacy in freshly extracted mice blood. Mechanistic studies show that both small molecules strongly bind fondaparinux in buffered water, as detected by fluorescence and NMR spectroscopy and confirmed by molecular dynamics simulations. Thus, these spermine derivatives are promising reversal agents against heparinoid anticoagulants with a wide range of molecular weights, overcoming the drawbacks of those antidotes based on biomacromolecules.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"1333–1346 1333–1346"},"PeriodicalIF":4.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00747","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficient Small-Molecule Reversal Agents for Anticoagulant Fondaparinux.","authors":"Daniel Carbajo, Yolanda Pérez, Gabriela F Castelo, Eva Prats, Jordi Bujons, Ignacio Alfonso","doi":"10.1021/acsptsci.4c00747","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00747","url":null,"abstract":"<p><p>Fondaparinux is a highly anionic synthetic heparinoid pentasaccharide used as an anticoagulant for specific clinical conditions and surgeries. As a non-natural small-molecule drug, it presents pharmacokinetic and pharmacodynamic advantages, as well as high stability and low immunogenicity, when compared with different forms of heparin. However, its broader usage is hampered by different factors like price, existence of alternative anticoagulants, or, specifically in this case, the lack of an effective antidote that is highly recommendable for avoiding uncontrolled bleeding. In this work, we describe two synthetic small molecules derived from spermine (3AC and 3FF) that efficiently revert the anticoagulant activity of fondaparinux. In an <i>in vitro</i> enzymatic assay related to blood coagulation, the spermine derivatives show potent activity as fondaparinux antidotes, with higher activity than ciraparantag (a small molecule in the clinical phase as an anticoagulant antidote) and much higher activity than protamine, the only approved antidote for unfractioned heparin but inefficient against fondaparinux. Remarkably, naked-eye <i>ex vivo</i> tests demonstrated their efficacy in freshly extracted mice blood. Mechanistic studies show that both small molecules strongly bind fondaparinux in buffered water, as detected by fluorescence and NMR spectroscopy and confirmed by molecular dynamics simulations. Thus, these spermine derivatives are promising reversal agents against heparinoid anticoagulants with a wide range of molecular weights, overcoming the drawbacks of those antidotes based on biomacromolecules.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 5","pages":"1333-1346"},"PeriodicalIF":4.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}