ChemMedChem最新文献_第8页

Exploiting the 5-Amino-11H-Indolo[3,2-c]isoquinoline Core to Achieve Better G-Quadruplex Ligands for Cancer Therapy 利用5-氨基- 11h -吲哚[3,2-c]异喹啉核心获得用于癌症治疗的更好的g -四联体配体。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-03-26 DOI: 10.1002/cmdc.202401019

Israa M. Aljnadi, Barbara Bahls, Noélia Duarte, Bruno L. Victor, Eduarda Mendes, Sergio P. Camões, Joana P. Miranda, Ermelinda Maçôas, Alexandra Paulo

{"title":"Exploiting the 5-Amino-11H-Indolo[3,2-c]isoquinoline Core to Achieve Better G-Quadruplex Ligands for Cancer Therapy","authors":"Israa M. Aljnadi, Barbara Bahls, Noélia Duarte, Bruno L. Victor, Eduarda Mendes, Sergio P. Camões, Joana P. Miranda, Ermelinda Maçôas, Alexandra Paulo","doi":"10.1002/cmdc.202401019","DOIUrl":"10.1002/cmdc.202401019","url":null,"abstract":"G-quadruplexes (G4) are secondary structures that can form within guanine-rich DNA sequences and have cell proliferation regulatory functions. Targeting DNA G4 structures has emerged as a promising anticancer therapy, highlighting the need for new G4 ligands with reduced number of cationic groups to ensure lower toxicity. Herein, the synthesis of mono- and di-substituted 5-amino-11H-indolo[3,2-c]isoquinolines is reported. Fluorescence spectroscopy studies indicate that substitution in position 11 dictates the preference of binding to different G4. Compound 10, which features an ethylpyrrolidine side chain, demonstrates a binding preference by one order of magnitude for parallel c-MYCG4 (Kb = 107 m−1), over parallel k-RASG4 (Kb = 106 m−1), and hybrid TeloG4 and dsDNA (Kb = 105 m−1). Molecular docking studies reveal that 10 can bind not only to the flat G-quartets but also to bridge between two loops of c-MYCG4 through hydrogen bonds, which may explain its capacity to discriminate between G4. Moreover, 10 drastically reduces the cell viability of breast cancer cells at a concentration of 10 μm. Overall, herein, the discovery of a new potent and selective G4 ligand, with reduced number of side chains and with antiproliferative activity in cancer cells, is reported, which deserves to be further investigated.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 11","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707851","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

Carborane-Based Analogs of Celecoxib and Flurbiprofen, their COX Inhibition Potential, and COX Selectivity Index 塞来昔布和氟比洛芬碳硼烷基类似物及其COX抑制电位和COX选择性指数。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-03-24 DOI: 10.1002/cmdc.202500166

Lea Ueberham, Jonas Schädlich, Kim Schramke, Sebastian Braun, Christoph Selg, Markus Laube, Peter Lönnecke, Jens Pietzsch, Evamarie Hey-Hawkins

{"title":"Carborane-Based Analogs of Celecoxib and Flurbiprofen, their COX Inhibition Potential, and COX Selectivity Index","authors":"Lea Ueberham, Jonas Schädlich, Kim Schramke, Sebastian Braun, Christoph Selg, Markus Laube, Peter Lönnecke, Jens Pietzsch, Evamarie Hey-Hawkins","doi":"10.1002/cmdc.202500166","DOIUrl":"10.1002/cmdc.202500166","url":null,"abstract":"The cylcooxygenase isoforms COX-1 and COX-2 are involved in the production of prostaglandins in physiological and pathological processes. The overexpression of COX-2 under inflammatory conditions, its role in cancer and neurodegenerative diseases necessitates the need to develop and improve nonsteroidal anti-inflammatory drugs. These mainly unselective COX inhibitors, e.g. aspirin, are used to reduce the symptoms of inflammation. To reduce unwanted side effects connected with unselective inhibition, the development of novel COX-2 selective inhibitors is a major goal. Herein, the synthesis, characterization and in vitro biological evaluation of eight flurbiprofen- and celecoxib-based carborane analogs are described. Carboranes as hydrophobic surrogates are suitable substituents that can contribute to a selectivity increase toward COX-2 due to size exclusion. The inhibitory efficacy for COX-1 and COX-2 of the four ortho- and four nido-carborane derivatives has been tested. The nido compounds are much more potent than their closo-carborane analogs. The celecoxib-based nido-carborane compound 10 shows an IC50(COX-2) value in the sub-μM range and slight selectivity for COX-2. This is in contrast to its ortho-carborane counterpart 9, which shows an inhibition preference for COX-1. While none of these carborane derivatives outperforms their organic analogs, the flurbiprofen-based nido-carborane derivatives 14a and 14b surpass the known carborane-based flurbiprofen analogs.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 11","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202500166","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699257","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

Nicorandil Repurposing in Orofacial Pain: Preclinical Findings in Adult Zebrafish 尼可地尔在口面部疼痛中的再利用：成年斑马鱼的临床前研究结果。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-03-22 DOI: 10.1002/cmdc.202401007

José Ismael Feitosa de Araújo, Gerlânia de Oliveira Leite, Antônio Eufrásio Vieira-Neto, Leonardo da Silva-Neto, Ângelo de Fátima, Adriana Rolim Campos

{"title":"Nicorandil Repurposing in Orofacial Pain: Preclinical Findings in Adult Zebrafish","authors":"José Ismael Feitosa de Araújo, Gerlânia de Oliveira Leite, Antônio Eufrásio Vieira-Neto, Leonardo da Silva-Neto, Ângelo de Fátima, Adriana Rolim Campos","doi":"10.1002/cmdc.202401007","DOIUrl":"10.1002/cmdc.202401007","url":null,"abstract":"This study investigates the orofacial antinociceptive activity of nicorandil in adult zebrafish and explores the involvement of TRP channels in this effect. Nicorandil, a known antianginal drug, reduces nociceptive behaviors induced by capsaicin (TRPV1 agonist), cinnamaldehyde (TRPA1 agonist), and menthol (TRPM8 agonist) without altering the locomotor activity of the zebrafish. Pretreatment with specific TRPA1 and TRPV1 antagonists prevents the antinociceptive effects of nicorandil, indicating its action on these channels. Molecular docking studies support these findings, demonstrating high chemical affinity and specific binding of nicorandil to the TRPV1 and TRPA1 channels, leading to stabilization and reduced biological activity of these channels. In contrast, the antinociceptive effect of nicorandil on menthol-induced nociception is not affected by a TRPM8 antagonist, suggesting that TRPM8 modulation is not involved in nicorandil's mechanism of action. The study highlights the potential of nicorandil as an analgesic through its interaction with TRPV1 and TRPA1 channels, providing a molecular basis for repositioning nicorandil as an effective analgesic drug.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 11","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690659","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

Two Targets, One Mission: Heterobivalent Metal-Based Radiopharmaceuticals for Prostate Cancer Imaging and Therapy 两个目标，一个任务：前列腺癌成像和治疗的异双价金属基放射性药物。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-03-21 DOI: 10.1002/cmdc.202500128

Margarida C. Sobral, Sandra I. Mota, Paulo J. Oliveira, Ana M. Urbano, António Paulo

{"title":"Two Targets, One Mission: Heterobivalent Metal-Based Radiopharmaceuticals for Prostate Cancer Imaging and Therapy","authors":"Margarida C. Sobral, Sandra I. Mota, Paulo J. Oliveira, Ana M. Urbano, António Paulo","doi":"10.1002/cmdc.202500128","DOIUrl":"10.1002/cmdc.202500128","url":null,"abstract":"Prostate cancer (PCa) is a significant healthcare challenge, associated with considerable mortality and morbidity among men, particularly in developed countries. PCa mortality and morbidity are primarily related to its most advanced form, metastatic castration-resistant PCa (mCRPC), for which there is presently no cure. Therefore, novel therapeutic approaches to increase mCRPC survival are critically needed. Due to PCa tumor heterogeneity and a complex tumor microenvironment, the efficacy of single-target radiopharmaceuticals, such as the Food and Drug Administration-approved [177Lu]Lu-PSMA-617, is currently under reassessment. The design and development of PCa dual-target radiopharmaceuticals have garnered considerable attention, due to their benefits over single-target counterparts, namely increased therapeutic specificity and efficacy, as well as the ability to overcome the challenge of inconsistent tumor visualization caused by variable receptor expression across diverse lesions, thereby enabling more comprehensive imaging. Several PCa biomarkers are currently being investigated as potential targets for dual-target radiopharmaceuticals, including prostate-specific membrane antigen, gastrin-releasing peptide receptor, integrin αvβ3 receptor, fibroblast activation protein, sigma-1 receptor, as well as albumin, the radiosensitive cell nucleus, and mitochondria. This review explores recent advancements in heterobivalent metal-based radiopharmaceuticals for dual targeting in PCa, highlighting their significance in theranostic and personalized medicine.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 11","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672999","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

Small-Molecule KRAS Inhibitors by Tyrosine Covalent Bond Formation. 酪氨酸共价键形成的小分子KRAS抑制剂。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-03-18 DOI: 10.1002/cmdc.202400624

Alexander D Landgraf, Robert Brenner, Mona K Ghozayel, Khuchtumur Bum-Erdene, Giovanni Gonzalez-Gutierrez, Samy O Meroueh

{"title":"Small-Molecule KRAS Inhibitors by Tyrosine Covalent Bond Formation.","authors":"Alexander D Landgraf, Robert Brenner, Mona K Ghozayel, Khuchtumur Bum-Erdene, Giovanni Gonzalez-Gutierrez, Samy O Meroueh","doi":"10.1002/cmdc.202400624","DOIUrl":"10.1002/cmdc.202400624","url":null,"abstract":"The development of the KRAS G12C inhibitor sotorasib is a major advance toward drugging KRAS. However, the G12C mutation is only found in about 10% of KRAS-driven tumors. KRAS possesses several tyrosine amino acids that could provide alternative sites for covalent drug development. Here, a library of aryl sulfonyl fluorides identified 1 (SOF-436) as an inhibitor of KRAS nucleotide exchange by guanine exchange factor SOS1 and KRAS binding to effector protein rapidly accelerated fibrosarcoma kinase (RAF). Tyr-64 is the major reaction site of 1 (SOF-436), although minor reaction at Tyr-71 is also observed. The fragment binds to the Switch II pocket of KRAS based on whole protein mass spectrometry, nucleotide exchange, effector protein binding, and nuclear magnetic resonance studies. Cocrystal structures of smaller fragments covalently bound to KRAS at Tyr-71 provide a strategy for the development of Switch I/II KRAS covalent inhibitors. A bioluminescent resonance energy transfer (NanoBRET) assay reveals that the compounds inhibit KRAS binding to RAF in mammalian cells. Although not yet suitable as chemical probes, these fragments provide starting points to develop small molecules to investigate tyrosine as a nucleophile for covalent inhibition of KRAS in tumors.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e2400624"},"PeriodicalIF":3.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655788","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 Novel Inhibitor against the Bromodomain Protein 1 of the Malaria Pathogen Plasmodium Falciparum 一种抗疟疾病原体恶性疟原虫溴结构域蛋白1的新型抑制剂。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-03-18 DOI: 10.1002/cmdc.202500024

Marius Amann, Robin Warstat, Kay Kristin Rechten, Philip Theuer, Magdalena Schustereder, Sophie Clavey, Bernhard Breit, Oliver Einsle, Martin Hügle, Michaela Petter, Stefan Günther

{"title":"A Novel Inhibitor against the Bromodomain Protein 1 of the Malaria Pathogen Plasmodium Falciparum","authors":"Marius Amann, Robin Warstat, Kay Kristin Rechten, Philip Theuer, Magdalena Schustereder, Sophie Clavey, Bernhard Breit, Oliver Einsle, Martin Hügle, Michaela Petter, Stefan Günther","doi":"10.1002/cmdc.202500024","DOIUrl":"10.1002/cmdc.202500024","url":null,"abstract":"The rise of drug resistances in malaria necessitates the exploration of novel therapeutic strategies. Targeting epigenetic pathways could open new, promising treatment avenues. In this study, the focus is on the essential Bromodomain protein 1 (PfBDP1) of the malaria pathogen Plasmodium falciparum. Utilizing the pan-selective bromodomain inhibitor MPM6, a potent initial hit is identified and it is subsequently developed into a nanomolar binder. Through a combination of virtual docking, isothermal titration calorimetry, and X-ray crystallography, the molecular interactions of the new inhibitors with the bromodomain (BRD) of the protein (PfBDP1-BRD) are elucidated. The findings include the first co-crystallized inhibitors with the structures of PfBRD1-BRD as well as the bromodomain of the close homologous protein of Plasmodium vivax (PvBDP1-BRD). The structures provide new insights into their binding mechanisms. Further validation using conditional knockdown of PfBDP1 in P. falciparum demonstrates parasite sensitivity to the inhibitor, underscoring its potential in a targeted therapeutic approach against malaria.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 11","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202500024","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655641","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

Advances in Diclofenac Derivatives: Exploring Carborane-Substituted N-Methyl and Nitrile Analogs for Anticancer Therapy 双氯芬酸衍生物的研究进展：碳硼烷取代n -甲基和腈类似物抗癌治疗的探索。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-03-18 DOI: 10.1002/cmdc.202500084

Christoph Selg, Robert Schuster, Aleksandr Kazimir, Peter Lönnecke, Mara Wolniewicz, Jonas Schädlich, Markus Laube, Jens Pietzsch, Vuk Gordić, Tamara Krajnović, Sanja Mijatović, Danijela Maksimović-Ivanić, Evamarie Hey-Hawkins

{"title":"Advances in Diclofenac Derivatives: Exploring Carborane-Substituted N-Methyl and Nitrile Analogs for Anticancer Therapy","authors":"Christoph Selg, Robert Schuster, Aleksandr Kazimir, Peter Lönnecke, Mara Wolniewicz, Jonas Schädlich, Markus Laube, Jens Pietzsch, Vuk Gordić, Tamara Krajnović, Sanja Mijatović, Danijela Maksimović-Ivanić, Evamarie Hey-Hawkins","doi":"10.1002/cmdc.202500084","DOIUrl":"10.1002/cmdc.202500084","url":null,"abstract":"This study explores the anticancer potential of N-methylated open-ring derivatives of carborane-substituted diclofenac analogs. By N-methylation, the open-chain form could be trapped and cyclization back to lactam or amidine derivatives is inhibited. A small library of carborane- and phenyl-based secondary and tertiary arylamines bearing carboxylic acid or nitrile groups is synthesized and analyzed for their COX affinity in vitro and in silico. The compounds are further evaluated against mouse adenocarcinoma (MC38), human colorectal carcinoma (HCT116), and human colorectal adenocarcinoma (HT29) cell lines and show potent cytotoxicity. Additional biological assessments of the mode of action are performed using flow cytometric techniques and fluorescence microscopy. The data obtained reveal a common antiproliferative effect coupled with the induction of caspase-independent apoptosis and the specific effects of the compound on the phenotype of MC38 cells, resulting in impaired cell viability of MC38 cells and satisfactory selectivity exceeding the antitumor activity of diclofenac.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 11","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202500084","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655770","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

Front Cover: Beyond the Toll-Like Receptor 4. Structure-Dependent Lipopolysaccharide Recognition Systems: How far are we? (ChemMedChem 6/2025) 封面：超越 Toll-Like 受体 4。结构依赖性脂多糖识别系统：我们还有多远？(ChemMedChem 6/2025)

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-03-16 DOI: 10.1002/cmdc.202580601

Stefania De Chiara, Luca De Simone Carone, Roberta Cirella, Dr. Emanuela Andretta, Prof. Alba Silipo, Prof. Antonio Molinaro, Dr. Marcello Mercogliano, Prof. Flaviana Di Lorenzo

{"title":"Front Cover: Beyond the Toll-Like Receptor 4. Structure-Dependent Lipopolysaccharide Recognition Systems: How far are we? (ChemMedChem 6/2025)","authors":"Stefania De Chiara, Luca De Simone Carone, Roberta Cirella, Dr. Emanuela Andretta, Prof. Alba Silipo, Prof. Antonio Molinaro, Dr. Marcello Mercogliano, Prof. Flaviana Di Lorenzo","doi":"10.1002/cmdc.202580601","DOIUrl":"https://doi.org/10.1002/cmdc.202580601","url":null,"abstract":"Gram-negative bacteria release lipopolysaccharides (LPS) into our bodies, acting as potent modulators of inflammation. These molecules can enhance or attenuate inflammation. Beyond the largely studied MD2/TLR4, a complex set of other receptors interact with LPS producing diverse effects. Understanding how the structural features of LPS affect the activity and crosstalk among various receptors is crucial for developing new drugs to treat immune-related pathologies. This review aims to persuade researchers with interest in this field to perform their research activities by always using a structure to function approach. More details can be found in article cmdc.202400780 by Marcello Mercogliano, Flaviana Di Lorenzo, and co-workers. \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture>\u0000 </div>\u0000 </figure>\u0000 ","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 6","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202580601","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632675","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

Cover Feature: Improving Affinity while Reducing Kidney Uptake of CXCR4-Targeting Radioligands Derived from the Endogenous Antagonist EPI-X4 (ChemMedChem 6/2025) 封面特征：内源性拮抗剂EPI-X4衍生的靶向cxcr4的放射配体在提高亲和力的同时减少肾脏摄取（ChemMedChem 6/2025）

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-03-16 DOI: 10.1002/cmdc.202580604

Dr. Raghuvir H. Gaonkar, Dr. Thibaud Bailly, Dr. Jacopo Millul, Dr. Rosalba Mansi, Dr. Mirja Harms, Prof. Dr. Jan Münch, Prof. Dr. Melpomeni Fani

引用次数: 0

Enhancing WRAP-Based Nanoparticles for Small Interfering Ribonucleic Acid Delivery in pH-Sensitive Environments 在ph敏感环境中增强基于wrap的siRNA递送纳米颗粒。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-03-14 DOI: 10.1002/cmdc.202400885

Giulia Di Gregorio, Coélio Vallée, Karidia Konate, Clémentine A. Teko-Agbo, Thania Hammoum, Héloïse Faure-Gautron, Yannick Bessin, Sebastien Deshayes, Eric Vivès, Albano C. Meli, Pascal de Santa Barbara, Sandrine Faure, Stéphanie Barrère-Lemaire, Sébastien Ulrich, Prisca Boisguérin

{"title":"Enhancing WRAP-Based Nanoparticles for Small Interfering Ribonucleic Acid Delivery in pH-Sensitive Environments","authors":"Giulia Di Gregorio, Coélio Vallée, Karidia Konate, Clémentine A. Teko-Agbo, Thania Hammoum, Héloïse Faure-Gautron, Yannick Bessin, Sebastien Deshayes, Eric Vivès, Albano C. Meli, Pascal de Santa Barbara, Sandrine Faure, Stéphanie Barrère-Lemaire, Sébastien Ulrich, Prisca Boisguérin","doi":"10.1002/cmdc.202400885","DOIUrl":"10.1002/cmdc.202400885","url":null,"abstract":"Small interfering RNAs (siRNA) are promising therapeutic molecules that require delivery systems to reach their targets. Several siRNA delivery systems, such as lipid- or peptide-based nanoparticles, are developed for different pathologies. In this context, we previously conceived a cell-penetrating peptide WRAP5-forming nanoparticles in the presence of siRNAsand validated the efficiency of this delivery system in inhibiting protein expression. In the pathophysiological context of acute myocardial infarction, which causes a pH drop in the ischemic heart tissue, we optimized the WRAP5-based nanoparticles for a pH-sensitive siRNA-targeted delivery. Therefore, pH-sensitive acyl hydrazone linkers are used to graft polyethylene (PEG) on the WRAP5 peptide. Proof of concept of the targeted delivery is performed using siRNA silencing the Fas-associated death domain (FADD)-containing protein implicated in apoptosis during myocardial ischemia-reperfusion injury on two human cell models (vascular endothelial cells and hiPSC-derived cardiomyocytes). The results show that only PEGylated WRAP5 nanoparticles via an appropriate acyl hydrazone linker can induce a specific FADD knockdown at pH 5 compared to naked nanoparticles. These optimized WRAP-based nanoparticles could be a novel therapeutic tool for treating myocardial infarction by inhibiting apoptosis induced by reperfusion and maximizing local delivery of the nanoparticle content at the site of injured cells.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"20 11","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202400885","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143622932","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