ChemMedChem最新文献_第3页

CORRIGENDUM: Carboranes as Potent Phenyl Mimetics: A Comparative Study on the Reversal of ABCG2-Mediated Drug Resistance by Carboranylquinazolines and Their Organic Isosteres. 勘误：碳硼烷作为有效的苯基模拟物：碳硼基喹唑啉及其有机同位体逆转abcg2介导的耐药的比较研究。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-14 Epub Date: 2024-12-03 DOI: 10.1002/cmdc.202400940

引用次数: 0

Adipocyte-Targeted Nanotechnology and Cell-Based Therapy for Obesity Treatment. 用于治疗肥胖症的脂肪细胞靶向纳米技术和细胞疗法。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-14 Epub Date: 2024-11-12 DOI: 10.1002/cmdc.202400611

Yue Wu, Siqi Deng, Siyu Wei, Wenqi Wei, Yunxiang He, Junling Guo

引用次数: 0

Selenocompounds as Potent Efflux Pump Inhibitors on Gram-positive Bacteria. 硒化合物作为革兰氏阳性细菌的强效外排泵抑制剂

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-14 Epub Date: 2024-11-20 DOI: 10.1002/cmdc.202400691

Annamária Kincses, Nikoletta Szemerédi, Miguel Benito-Lama, Dávid Dózsai, Ákos Csonka, Enrique Domínguez-Álvarez, Gabriella Spengler

{"title":"Selenocompounds as Potent Efflux Pump Inhibitors on Gram-positive Bacteria.","authors":"Annamária Kincses, Nikoletta Szemerédi, Miguel Benito-Lama, Dávid Dózsai, Ákos Csonka, Enrique Domínguez-Álvarez, Gabriella Spengler","doi":"10.1002/cmdc.202400691","DOIUrl":"10.1002/cmdc.202400691","url":null,"abstract":"In recent years, selenocompounds have gained increasing attention as potential anticancer and antibacterial agents. Several selenoderivatives have been confirmed to act as MDR efflux pump inhibitors, based on their in vitro results against the bacterial AcrAB-TolC system and the cancer MDR efflux pump P-glycoprotein. Efflux pumps can contribute directly or indirectly to the virulence of bacteria, as they can reduce the intracellular concentration of antibacterial substances by expelling them out of the cell. The present work aims to study the antibacterial and efflux pump inhibiting properties of four families of selenoesters, namely aspirin-selenoesters, phenone-selenoesters, hydroxy-selenoesters, and benzyl-selenoesters. The real-time ethidium bromide accumulation assay confirmed that these derivatives inhibited the efflux systems of methicillin-resistant Staphylococcus aureus (MRSA) without exerting any antibacterial effect. The relative expression of efflux pump gene of NorA transporter was also monitored in the presence of the most potent derivatives on reference S. aureus, finding that these derivatives could change the expression of the tested efflux pump gene. Regarding the anti-biofilm activity, aspirin-selenoesters, benzyl-selenoesters, and hydroxy-selenoesters could efficiently inhibit the biofilm production of the MRSA strain. It can be concluded that selenocompounds could act as efflux pump inhibitors, thus reducing the virulence of biofilm-producing bacteria.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400691"},"PeriodicalIF":3.6,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674656","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

Towards New Anti-Inflammatory Agents: Design, Synthesis and Evaluation of Molecules Targeting XIAP-BIR2. 开发新的抗炎药物：靶向 XIAP-BIR2 分子的设计、合成和评估。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-14 Epub Date: 2024-11-12 DOI: 10.1002/cmdc.202400567

Marc Farag, Nicolas Guedeney, Florian Schwalen, Aymeric Zadoroznyj, Amélie Barczyk, Martin Giret, Kevin Antraygues, Alice Wang, Marie Cornu, Peggy Suzanne, Marc Since, Anne Sophie Voisin-Chiret, Laurence Dubrez, Natascha Leleu-Chavain, Charline Kieffer, Jana Sopkova-de Oliveira Santos

{"title":"Towards New Anti-Inflammatory Agents: Design, Synthesis and Evaluation of Molecules Targeting XIAP-BIR2.","authors":"Marc Farag, Nicolas Guedeney, Florian Schwalen, Aymeric Zadoroznyj, Amélie Barczyk, Martin Giret, Kevin Antraygues, Alice Wang, Marie Cornu, Peggy Suzanne, Marc Since, Anne Sophie Voisin-Chiret, Laurence Dubrez, Natascha Leleu-Chavain, Charline Kieffer, Jana Sopkova-de Oliveira Santos","doi":"10.1002/cmdc.202400567","DOIUrl":"10.1002/cmdc.202400567","url":null,"abstract":"The X-chromosome-linked inhibitor of apoptosis protein (XIAP) plays a crucial role in controlling cell survival across multiple regulated cell death pathways and coordinating a range of inflammatory signalling events. The discovery of selective inhibitors for XIAP-BIR2, able to disrupt the direct physical interaction between XIAP and RIPK2, offer promising therapeutic options for NOD2-mediated diseases like Crohn's disease, sarcoidosis, and Blau syndrome. The objective of this study was to design, synthesize, and evaluate small synthetic molecules with binding selectivity to XIAP-BIR2 domain. To achieve this, we applied an interdisciplinary drug design approach and firstly we have synthesized an initial fragment library to achieve a first XIAP inhibition activity. Then using a growing strategy, larger compounds were synthesized and one of them presents a good selectivity for XIAP-BIR2 versus XIAP-BIR3 domain, compound 20 c. The ability of compound 20 c to block the NOD1/2 pathway was confirmed in cell models. These data show that we have synthesized molecules capable of blocking NOD1/2 signalling pathways in cellulo, and ultimately leading to new anti-inflammatory compounds.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400567"},"PeriodicalIF":3.6,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370375","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

Conformational Engineering of Flexible Protein Fragments on the Surface of Different Nanoparticles: The Surface-Atom Mobility Rules. 不同纳米颗粒表面柔性蛋白片段的构象工程：表面-原子迁移规律。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-14 DOI: 10.1002/cmdc.202400832

Wenxian Zhao, Yiwei Sun, Laiyu Che, Haifang Wang, Aoneng Cao

{"title":"Conformational Engineering of Flexible Protein Fragments on the Surface of Different Nanoparticles: The Surface-Atom Mobility Rules.","authors":"Wenxian Zhao, Yiwei Sun, Laiyu Che, Haifang Wang, Aoneng Cao","doi":"10.1002/cmdc.202400832","DOIUrl":"https://doi.org/10.1002/cmdc.202400832","url":null,"abstract":"As a newly emerging technology, conformational engineering (CE) has been gradually displaying the power of producing protein-like nanoparticles (NPs) by tuning flexible protein fragments into their original native conformation on NPs. But apparently, not all types of NPs can serve as scaffolds for CE. To expedite the CE technology on a broader variety of NPs, the essential characteristic of NPs as scaffolds for CE needs to be identified. Herein, we investigate the potential of two distinct types of NPs as scaffolds for CE: CdSe/ZnS quantum dots (QDs), an ionic compound NP, and palladium NPs (PdNPs), a metal NP. The results demonstrate that while QDs cannot support the restoration of the native conformation and function of the complementary-determining region (CDR) fragments of antibodies, PdNPs can. The notably disparate outcomes unequivocally show that the mobility of the surface atoms/adatoms of the NPs or the mobility of the conjugating bonds to the NPs is essential for CE, which allows the conjugated peptides to undergo a conformational change from their initial random conformation to their most stable native conformation under the constraints mimicking the native long-range interactions in the original proteins. This discovery opens the door for CE on more NPs in the future.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400832"},"PeriodicalIF":3.6,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982181","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

De Novo Design of Tryptophan Containing Broad-Spectrum Cationic Antimicrobial Octapeptides. 从头设计含色氨酸的广谱阳离子抗菌八肽。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-14 Epub Date: 2024-11-13 DOI: 10.1002/cmdc.202400566

Tanumoy Sarkar, S R Vignesh, Pradeep Kumar Sundaravadivelu, Rajkumar P Thummer, Priyadarshi Satpati, Sunanda Chatterjee

{"title":"De Novo Design of Tryptophan Containing Broad-Spectrum Cationic Antimicrobial Octapeptides.","authors":"Tanumoy Sarkar, S R Vignesh, Pradeep Kumar Sundaravadivelu, Rajkumar P Thummer, Priyadarshi Satpati, Sunanda Chatterjee","doi":"10.1002/cmdc.202400566","DOIUrl":"10.1002/cmdc.202400566","url":null,"abstract":"With the advent of antibiotic resistant organisms, development of alternate classes of molecules other than antibiotics to combat microbial infections, have become extremely important. In this context, antimicrobial peptides have taken center stage of antimicrobial therapeutic research. In this work, we have reported two cationic antimicrobial octapeptides WRL and LWRF, with broad spectrum antimicrobial activities against several strains of ESKAPE pathogens. Both the peptides were membrane associative and induced microbial cell death through membranolysis, being selective towards microbial membranes over mammalian membranes. The AMPs were unstructured in water, adopting partial helical conformation in the presence of microbial membrane mimics. Electrostatic interaction formed the primary basis of peptide-membrane interactions. WRL was more potent, salt tolerant and faster acting of the two AMPs, owing to the presence of two tryptophan residues against that of one in LWRF. Increased tryptophan number in WRL enhanced its membrane association ability, resulting in higher antimicrobial potency but lower selectivity. This experimental and computational work, established that an optimum number of tryptophan residues and their position was critical for obtaining high antimicrobial potency and selectivity simultaneously in the designed cationic AMPs. Understanding the peptide membrane interactions in atomistic details can lead to development of better antimicrobial therapeutics in future.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400566"},"PeriodicalIF":3.6,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454108","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

Acetic Acid-Driven One-Pot Synthesis of 4,7-dihydro-[1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxamides and Pharmacological Evaluations. 乙酸驱动的 4,7-二氢-[1,2,3]噻二唑并[5,4-b]吡啶-6-羧酰胺的单锅合成及药理评价。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-14 Epub Date: 2024-11-13 DOI: 10.1002/cmdc.202400595

Savan S Bhalodiya, Mehul P Parmar, Chirag D Patel, Subham G Patel, Disha P Vala, Nandhakumar Suresh, Bhuvaneshwari Jayachandran, Madan Kumar Arumugam, Mahesh Narayan, Hitendra M Patel

{"title":"Acetic Acid-Driven One-Pot Synthesis of 4,7-dihydro-[1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxamides and Pharmacological Evaluations.","authors":"Savan S Bhalodiya, Mehul P Parmar, Chirag D Patel, Subham G Patel, Disha P Vala, Nandhakumar Suresh, Bhuvaneshwari Jayachandran, Madan Kumar Arumugam, Mahesh Narayan, Hitendra M Patel","doi":"10.1002/cmdc.202400595","DOIUrl":"10.1002/cmdc.202400595","url":null,"abstract":"A diverse set of 4,7-dihydro-[1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxamides 4(a-o) was synthesized via a one-pot reaction of 5-amino-[1,2,3]thiadiazole, various aromatic aldehydes, and different acetoacetanilides, using glacial acetic acid. The resulting compounds were obtained in moderate to good yields. All the newly synthesized compounds were evaluated for their antimicrobial activity. Among them, compound 4 e demonstrated superior efficacy against the Salinivibrio proteolyticus strain of Gram-negative bacteria compared to ciprofloxacin. Compound 4 d exhibited the highest potency against the fungal strain Candida albicans, surpassing amphotericin B. The physicochemical characteristics of 4 d and 4 e were assessed. According to docking analysis, DHTDAPy 4 e shows a higher binding affinity of -7.2 kcal/mol in the binding cavity of the receptor. These findings illustrate the safety, tolerability, and potency of the newly synthesized DHTDAPy compounds against fungal and bacterial infections.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400595"},"PeriodicalIF":3.6,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454106","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

Exploring the Utility of Cell-Penetrating Peptides as Vehicles for the Delivery of Distinct Antimalarial Drug Cargoes. 探索细胞穿透肽作为输送不同抗疟药物载体的实用性。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-14 Epub Date: 2024-11-12 DOI: 10.1002/cmdc.202400637

Caitlin L Gare, Isabella R Palombi, Andrew M White, Marina Chavchich, Michael D Edstein, Aaron Lock, Vicky M Avery, David J Craik, Brendan J McMorran, Nicole Lawrence, Lara R Malins

{"title":"Exploring the Utility of Cell-Penetrating Peptides as Vehicles for the Delivery of Distinct Antimalarial Drug Cargoes.","authors":"Caitlin L Gare, Isabella R Palombi, Andrew M White, Marina Chavchich, Michael D Edstein, Aaron Lock, Vicky M Avery, David J Craik, Brendan J McMorran, Nicole Lawrence, Lara R Malins","doi":"10.1002/cmdc.202400637","DOIUrl":"10.1002/cmdc.202400637","url":null,"abstract":"The devastating impact of malaria includes significant mortality and illness worldwide. Increasing resistance of the causative parasite, Plasmodium, to existing antimalarial drugs underscores a need for additional compounds with distinct modes of action in the therapeutic development pipeline. Here we showcase peptide-drug conjugates (PDCs) as an attractive compound class, in which therapeutic or lead antimalarials are chemically conjugated to cell-penetrating peptides. This approach aims to enhance selective uptake into Plasmodium-infected red blood cells and impart additional cytotoxic actions on the intraerythrocytic parasite, thereby enabling targeted drug delivery and dual modes of action. We describe the development of PDCs featuring four compounds with antimalarial activity-primaquine, artesunate, tafenoquine and methotrexate-conjugated to three cell-penetrating peptide scaffolds with varied antiplasmodial activity, including active and inactive analogues of platelet factor 4 derived internalization peptide (PDIP), and a cyclic polyarginine peptide. Development of this diverse set of PDCs featured distinct and adaptable conjugation strategies, to produce conjugates with in vitro antiplasmodial activities ranging from low nanomolar to low micromolar potencies according to the drug cargo and bioactivity of the partner peptide. Overall, this study establishes a strategic and methodological framework for the further development of dual mode of action peptide-drug antimalarial therapeutics.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400637"},"PeriodicalIF":3.6,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386680","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

Targeting Tetraspanins at Cell Interfaces: Functional Modulation and Exosome-Based Drug Delivery for Precise Disease Treatment. 在细胞界面靶向四泛素：功能调节和基于外泌体的药物输送，实现精准疾病治疗。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-14 Epub Date: 2024-11-14 DOI: 10.1002/cmdc.202400664

Kun Xu, Huixia Feng, Rui Zhao, Yanyan Huang

{"title":"Targeting Tetraspanins at Cell Interfaces: Functional Modulation and Exosome-Based Drug Delivery for Precise Disease Treatment.","authors":"Kun Xu, Huixia Feng, Rui Zhao, Yanyan Huang","doi":"10.1002/cmdc.202400664","DOIUrl":"10.1002/cmdc.202400664","url":null,"abstract":"Tetraspanins are key players in various physiological and pathological processes, including malignancy, immune response, fertilization, and infectious disease. Affinity ligands targeting the interactions between tetraspanins and partner proteins are promising for modulating downstream signaling pathways, thus emerging as attractive candidates for interfering related biological functions. Due to the involvement in vesicle biogenesis and cargo trafficking, tetraspanins are also regarded as exosome markers, and become molecular targets for drug loading and delivery. Given the rapid development in these areas, this minireview focuses on recent advances in design and engineering of affinity binders toward tetraspanins including CD63, CD81, and CD9. Their mechanism of actions in modulating protein interactions at cell interfaces and treatment of malignant diseases are discussed. Strategies for constructing exosome-based drug delivery platforms are also reviewed, with emphasis on the important roles of tetraspanins and the affinity ligands. Finally, challenges and future development of tetraspanin-targeting therapy and exosomal drug delivery platforms are also discussed.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400664"},"PeriodicalIF":3.6,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454113","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

Structure and dynamics of monoclonal antibody domains determined using spins, scattering, and simulations. 单克隆抗体结构域的结构和动力学使用自旋，散射和模拟确定。

IF 3.6 4区医学

ChemMedChem Pub Date : 2025-01-13 DOI: 10.1002/cmdc.202400917

Veronika A Szalai, Christina Bergonzo, Rachel Lyon, Zvi Kelman, Thomas Schmidt, Alexander Grishaev

{"title":"Structure and dynamics of monoclonal antibody domains determined using spins, scattering, and simulations.","authors":"Veronika A Szalai, Christina Bergonzo, Rachel Lyon, Zvi Kelman, Thomas Schmidt, Alexander Grishaev","doi":"10.1002/cmdc.202400917","DOIUrl":"https://doi.org/10.1002/cmdc.202400917","url":null,"abstract":"Antibody-based pharmaceuticals are the leading biologic drug platform (> $75B/year). Despite a wealth of information collected on them, there is still a lack of knowledge on their inter-domain structural distributions, which impedes innovation and development. To address this measurement gap, we have developed a new methodology to derive biomolecular structure ensembles from distance distribution measurements via a library of tagged proteins bound to an unlabeled and otherwise unmodified target biologic. We have employed the NIST monoclonal antibody (NISTmAb) reference material as our development platform for use with spin-labeled affinity protein (SLAP) reagents. Using double electron-electron resonance (DEER) spectroscopy, we have determined inter-spin distance distributions in SLAP complexes of both the isolated Fc domain and the intact NISTmAb. Our SLAP reagents offer a general and extendable technology, compatible with any non-isotopically labeled immunoglobulin G class mAb. Integrating molecular simulations with the DEER and solution X-ray scattering measurements, we enable simultaneous determination of structural distributions and dynamics of mAb-based biologics.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":" ","pages":"e202400917"},"PeriodicalIF":3.6,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968991","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