Bioorganic & Medicinal Chemistry最新文献

{"title":"Antiviral activities of phenylalanine derivatives carrying carboxylic acid bioisosteres against chikungunya and parainfluenza virus type 3","authors":"Merve Camcı Eren ,&nbsp;Görkem Güngör ,&nbsp;Steven De Jonghe ,&nbsp;Dirk Jochmans ,&nbsp;Mehmet Özbil ,&nbsp;Johan Neyts ,&nbsp;Suzanne Kaptein ,&nbsp;Halil Şenol ,&nbsp;Aytekin Köse ,&nbsp;Mikail Hakan Gezginci ,&nbsp;Nilgün Karalı","doi":"10.1016/j.bmc.2025.118343","DOIUrl":"10.1016/j.bmc.2025.118343","url":null,"abstract":"<div><div>Pathogenic RNA viruses from various virus families represent substantial public health hazards. Specific antiviral drugs effective against most RNA virus infections have not yet been developed. In this study, it was aimed to investigate the broad-spectrum antiviral activities of phenylalanine derivatives designed by replacing the carboxylic acid moiety with various bioisosteres such as nitrile, hydroxamidine and 5-oxo/thioxo-1,2,4-oxadiazole. Novel synthesized <em>N</em>-(1-substituted 2-phenylethyl)-<em>N</em>-(3-chlorobenzyl)-2,4-dichlorobenzamides (<strong>6e</strong>, <strong>7e</strong>, <strong>8e</strong> and <strong>9d</strong>), together with phenylalanine derivatives previously prepared by our group, were evaluated antiviral activities against chikungunya (CHIKV), Zika (ZIKV), parainfluenza virus type 3 (PIV3), and enterovirus 71 (EV71). All phenylalanine derivatives showed antiviral activities against PIV3, with the 3-fluorobenzyl substituted analogue <strong>6d</strong> emerging as the most potent compound (IC₅₀ = 3.74 μM, CC₅₀ &gt; 100 μM), whereas the 3-chlorobenzyl analogue <strong>6e</strong> (IC₅₀ = 5.72 μM, CC₅₀ &gt; 100 μM) possessed the best non-toxic antiviral activity against CHIKV. Combined molecular docking and molecular dynamics (MD) simulation studies were conducted to predict the interactions of compounds <strong>6d</strong> and <strong>6e</strong> with the possible viral proteins of PIV3 and CHIKV, respectively.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118343"},"PeriodicalIF":3.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144828452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and biological evaluation of C-ring nitro-substituted dehydroabietylamine analogs: in vitro cytotoxicity, DNA affinity, and molecular docking studies","authors":"Huayu Xue ,&nbsp;Zhenzhen Gu ,&nbsp;Lin Li ,&nbsp;Wen Lu ,&nbsp;Shilong Yang ,&nbsp;Li Xu ,&nbsp;Zhong Li","doi":"10.1016/j.bmc.2025.118349","DOIUrl":"10.1016/j.bmc.2025.118349","url":null,"abstract":"<div><div>In pursuit of more effective anticancer treatments, we developed a series of innovative dehydroabietylamine (<strong>DHAA</strong>) derivatives, with particular emphasis on introducing nitro modifications to the C-ring based on incorporating C-18 Schiff base heterocyclic structures. We evaluated the cytotoxic effects of these compounds in vitro against a panel of human tumor cell lines – MCF-7 (breast cancer), A549 (lung cancer), HeLa (cervical cancer), and HepG2 (liver cancer) - as well as the non-malignant cell line HUVEC (human umbilical vein endothelial cells). <strong>DHAA</strong> derivatives <strong>L</strong>^{<strong>15</strong>} and <strong>L</strong>^{<strong>20</strong>}, with C-ring 14-nitro substitution based on C-18 Schiff base heterocyclic modification, showed higher cytotoxic activity against HeLa and A549 cells, respectively, while demonstrating significantly lower cytotoxicity to non-malignant HUVEC cells. Meantime the mechanism of cytotoxicity of <strong>DHAA</strong> derivatives was preliminarily investigated. The result suggested that inducing cell apoptosis might be the primary mechanism. The interaction between <strong>DHAA</strong> derivatives and HS-DNA was studied using absorption spectral analysis and ethidium bromide (EB) fluorescence displacement experiments, the results exhibited that the binding of <strong>DHAA</strong> derivatives to DNA was in the intercalative mode. The molecular docking study demonstrated that <strong>DHAA</strong> derivatives exhibited a strong binding affinity to DNA, facilitated by carbon‑hydrogen interactions and π-donor hydrogen bonds. The structure-activity relationship discussion implied that introduction of the nitro-group, especially the 14-nitro group, significantly improved the cytotoxicity of <strong>DHAA</strong>. The significant cytotoxicity and high selectivity exhibited by compounds <strong>L</strong>^{<strong>15</strong>} and <strong>L</strong>^{<strong>20</strong>} suggested their potential as promising antitumor medicines.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118349"},"PeriodicalIF":3.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144828454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Virtual screening, synthesis, optimization and anti-inflammatory activity of novel chromones as specific COX-2 inhibitors","authors":"Meng Qin,&nbsp;Mengdi Zhang,&nbsp;Min Wang,&nbsp;Huiqing Guo,&nbsp;Laibing Wang,&nbsp;Jianping Chen,&nbsp;Shuyan Yu,&nbsp;Yuheng Ma","doi":"10.1016/j.bmc.2025.118345","DOIUrl":"10.1016/j.bmc.2025.118345","url":null,"abstract":"<div><div>In this study, we pioneered the use of SMARTS screening to construct a chromone database, and the Discovery Studio was used to achieve precise molecular docking of COX-2 through LibDock and CDOCKER, and successfully locked 7 hit compounds from the massive chromone library. In cell experiments, <strong>Q7</strong> had a significant inhibitory effect on LPS-induced PGE₂ (IC₅₀ = 68.23 ± 8.94 μM) and NO (IC₅₀ = 44.83 ± 2.01 μM) in RAW264.7 cells, and its anti-inflammatory activity was superior to that of the traditional anti-inflammatory agents <strong>ibuprofen</strong> [IC₅₀(PGE₂) = 246.5 ± 3.8 μM] and <strong>L-canavanine</strong> [IC₅₀(NO) = 440.0 ± 7.9 μM]. Still, the activity was not as good as that of <strong>celecoxib</strong> [IC₅₀ (PGE₂) = 0.882 ± 0.021 μM], and the western blot of <strong>Q7</strong> further confirmed its targeted inhibition of COX-2. On this basis, the structure of <strong>Q7</strong> was optimized by flexible docking design, and 30 <strong>Q7</strong> derivatives were synthesized one by one, all of which showed certain anti-inflammatory activities, among which <strong>Q7–9</strong> [IC₅₀(PGE₂) = 0.209 ± 0.022 μM, IC₅₀(COX-2) = 0.121 ± 0.010 μM], <strong>Q7–25</strong> [IC₅₀(PGE₂) = 0.267 ± 0.017 μM, IC₅₀(COX-2) = 0.228 ± 0.021 μM] and <strong>Q7–26</strong> [IC₅₀(PGE₂) = 0.161 ± 0.018 μM, IC₅₀(COX-2) = 0.137 ± 0.004 μM] exhibited anti-inflammatory activity better than celecoxib and had a moderate selectivity index (SI_{<strong>Q7</strong>}_{<strong>–</strong>}_{<strong>9</strong>} &gt; 826). <strong>Q7–28</strong> (IC₅₀ = 0.014 ± 0.001 μM) and <strong>Q7–29</strong> (IC₅₀ &lt; 0.0128 μM) had significant inhibitory effects on NO. In addition, by constructing a 3D-QSAR model, the anti-inflammatory structures of chromone and isoflavone molecules for COX-2 and iNOS targets were systematically revealed. This study provided an important reference and basis for the research and development of new chromone non-steroidal anti-inflammatory drugs, and <strong>Q7–9</strong> was expected to be a candidate drug with high safety and specific COX-2 inhibitors.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118345"},"PeriodicalIF":3.0,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144828453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unravelling the potential of small molecule tumor necrosis factor-α (TNF) inhibitors: A comprehensive review","authors":"Yaman Chauhan,&nbsp;Akshay Kumawat,&nbsp;Abhay Singh,&nbsp;Nagula Shankaraiah,&nbsp;Venkata Rao Kaki","doi":"10.1016/j.bmc.2025.118344","DOIUrl":"10.1016/j.bmc.2025.118344","url":null,"abstract":"<div><div>TNF-α is a key cytokine, plays a critical role in the pathogenesis of autoimmune and inflammatory diseases such as rheumatoid arthritis and psoriasis. As a result, TNF-α has emerged as a pivotal therapeutic target. Currently, monoclonal antibodies and decoy receptors targeting TNF-α are widely used, yet they face limitations such as administration challenges. These drawbacks have driven the exploration of small molecule inhibitors as alternative therapeutic agents due to their oral bioavailability, ability to cross biological barriers, and cost-effective production. Significant efforts have been directed toward developing small-molecule TNF-α inhibitors, which function either by disrupting the TNF trimer or by blocking TNF-αTNFR interactions. Several candidates have progressed to clinical trials, demonstrating their potential as therapeutic agents. This review provides a comprehensive overview of TNF-α small-molecule inhibitors, covering their discovery, design strategies, structure-activity relationships, and biological evaluation. Additionally, it discusses current clinical outcomes and outlook to guide researchers in the drug design and development of more potent inhibitors.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118344"},"PeriodicalIF":3.0,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144842604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small phenolic inhibitors of PfATP6, a Plasmodium falciparum calcium ATPase, as prototype antimalarials","authors":"Sydni Sobota ,&nbsp;Shiffany Devaraja ,&nbsp;Matthew Chung ,&nbsp;Justin Arevalo ,&nbsp;Jonathan Martinez-Aguirre ,&nbsp;Jastina Makeyenko ,&nbsp;Cynthia Kellen-Yuen ,&nbsp;Sam Eastman ,&nbsp;Emily Derbyshire ,&nbsp;Christelle Saade ,&nbsp;Thibaud Dieudonné ,&nbsp;Stefan Paula","doi":"10.1016/j.bmc.2025.118342","DOIUrl":"10.1016/j.bmc.2025.118342","url":null,"abstract":"<div><div>Malaria, an infectious disease caused by <em>Plasmodium</em> parasites, continues to pose a serious global health problem. PfATP6, a calcium-transporting transmembrane protein present in <em>Plasmodium falciparum</em>, has been identified as a promising target for new antimalarial drugs, prompting searches for specific and potent inhibitors of this enzyme. Such compounds also have the potential of becoming novel research tools for the elucidation of the enzyme's physiological functions. However, only a few PfATP6 inhibitors are known to date and most of them suffer from limitations due to their high structural complexity, with high costs that restrict their availability. A notable exception is a group of structurally simple phenolic compounds that feature hydroquinone and naphthoquinone scaffolds. In order to assess the potential of this compound class as future antimalarials, we characterized a small library of these molecules in <em>P. falciparum</em> blood stage viability and PfATP6 activity inhibition assays. Several compounds were able to inhibit parasite growth, amongst them di-alkylated hydroquinones, a naphthoquinone disulfide, and hexachlorophene, a disinfectant. Some of the antiplasmodial compounds were also able to inhibit the activity of the purified enzyme, even though the correlation between these two properties was not absolute. The molecular interactions of active compounds with PfATP6 were analyzed by homology modeling, ligand docking, and molecular dynamics simulations, revealing a combination of hydrogen bonding and hydrophobic interactions as the main contributors to binding. The gained information constitutes a first step toward the future design of small-molecule PfATP6 inhibitors with improved properties.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"Article 118342"},"PeriodicalIF":3.0,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging chemistries in proximity labeling","authors":"Bella M. Ben-Oz ,&nbsp;Nir Hananya","doi":"10.1016/j.bmc.2025.118339","DOIUrl":"10.1016/j.bmc.2025.118339","url":null,"abstract":"<div><div>Proximity labeling (PL) has transformed the study of biomolecular interactions by enabling the covalent tagging of molecules near a protein of interest in living cells. This review outlines recent advances in PL chemistries over the recent years, focusing on novel enzyme-based and photocatalytic approaches. These emerging tools overcome limitations of traditional methods, enabling precise mapping of cellular interactomes across diverse biological contexts. We discuss their mechanisms, various applications, and the associated trade-offs regarding specificity and applicability, underscoring their potential to enhance the study of biomolecular networks.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"Article 118339"},"PeriodicalIF":3.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144780264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rational design, synthesis, and evaluating primary biological activities of novel HIV-1 protease inhibitors containing heteraryl acetamides as the P2 ligands","authors":"Sihan Meng ,&nbsp;Yu Gao ,&nbsp;Qingqing Yang ,&nbsp;Ling Ma ,&nbsp;Biao Dong ,&nbsp;Juxian Wang ,&nbsp;Guoning Zhang ,&nbsp;Minghua Wang ,&nbsp;Shan Cen ,&nbsp;Mei Zhu ,&nbsp;Qi Shan ,&nbsp;Yucheng Wang","doi":"10.1016/j.bmc.2025.118338","DOIUrl":"10.1016/j.bmc.2025.118338","url":null,"abstract":"<div><div>A series of novel potent HIV-1 protease inhibitors featuring diverse hydroxyaromatic acetanilide derivatives as P2 ligands and 4-substituted phenyl sulfonamides as P2’ ligands were designed, synthesized, and biologically evaluated. The majority of the target compounds demonstrated potent enzyme inhibitory activity with IC₅₀ values below100 nM. Notably, compound <strong>18h</strong>, incorporating a 2-(4-hydroxypyrimidin-5-yl) acetamide P2 ligand and a 4-methoxybenzenesulfonamide as the P2’ ligand, exhibited exceptional potency with an enzyme IC₅₀ of 0.46 nM and antiviral EC₅₀ of 0.26 μM against HIV-1_NL4_–₃ strain. In addition, <strong>18h</strong> displayed activity with EC₅₀ value of 0.25 μM against the subtype C HIV-1 Indie strain. The extensive hydrogen-bonding interactions with the protease active site revealed in the molecular docking analysis of <strong>18h</strong>-bound HIV-1 protease provided valuable structural insights for the rational design of next-generation HIV-1 protease inhibitors.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"Article 118338"},"PeriodicalIF":3.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and lipid-lowering activities of preussin derivatives","authors":"Kwanruthai Tadpetch ,&nbsp;Kittisak Thongpat ,&nbsp;Nalinrat Jeensrikong ,&nbsp;Nisachol Permrungreang ,&nbsp;Pannita Holasut ,&nbsp;Worarat Rojanaverawong ,&nbsp;Thanthakan Saithong ,&nbsp;Kornwalai Tunkaew ,&nbsp;Vatcharin Rukachaisirikul ,&nbsp;Chutima S. Vaddhanaphuti","doi":"10.1016/j.bmc.2025.118336","DOIUrl":"10.1016/j.bmc.2025.118336","url":null,"abstract":"<div><div>Syntheses of eleven natural and unnatural analogues of preussin, a pyrrolidin-3-ol alkaloid, have been achieved starting from <em>L</em>-phenylalanine. Our work highlighted an efficient strategy to construct the all <em>cis</em> pyrrolidin-3-ols bearing functionalized alkyl side chain via the key Sakurai allylation and cross metathesis reaction which led to the first syntheses of six other preussin analogues including the four natural products, preussins F, G, H and I. The eleven synthetic analogues were evaluated for their inhibitory effects on cholesterol absorption using fluorescent-cholesterol transport assay in human intestinal Caco-2 cells. All analogues at 5 μg/mL statistically reduced cholesterol absorption comparable to 40 μg/mL of a positive drug, ezetimibe, without cytotoxic effect to the Caco-2 cells. Synthetic preussin B exhibited the highest potency of 18.6 % reduction. The synthetic analogues were further evaluated for lipid-lowering effects in human hepatocellular carcinoma HepG2 cells via the expression of five genes related to hepatic lipid metabolism and pro-inflammatory cytokines using real-time PCR. Remarkably, preussin B significantly modulated hepatic lipid metabolism genes by down-regulating HMGR and up-regulating PPARα, rendering preussin B a new and promising candidate for hypolipidemic and hepatic lipid-lowering agent. Nevertheless, the parent compound, preussin, exhibited the most potent antioxidative effect by markedly scavenging intracellular reactive oxygen species in H₂O₂-induced oxidative stress condition in both Caco-2 and HepG2 cell lines.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"Article 118336"},"PeriodicalIF":3.0,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generation of a potent & selective series of IRAK4 inhibitors based on a structure based, hybridization approach","authors":"Ina Terstiege ,&nbsp;Anna Aagaard ,&nbsp;Kristina Berggren ,&nbsp;James Bird ,&nbsp;Iain A. Cumming ,&nbsp;Sam D. Groombridge ,&nbsp;Lotta Hidestål ,&nbsp;Petra Johannesson ,&nbsp;Pernilla Korsgren ,&nbsp;Karl-Johan Leuchowius ,&nbsp;Sara Lundqvist ,&nbsp;James S. Scott ,&nbsp;Yafeng Xue ,&nbsp;Sébastien L. Degorce","doi":"10.1016/j.bmc.2025.118333","DOIUrl":"10.1016/j.bmc.2025.118333","url":null,"abstract":"<div><div>IRAK4 inhibitors are of high interest as treatment for not only inflammatory and autoimmune diseases, but also in the field of oncology. Despite extensive research in the IRAK4 area and progression of several inhibitors into clinical trials, no IRAK4 inhibitor has yet reached the market. In this article, we describe the development of a highly potent and selective IRAK4 lead compound <strong>5e</strong>, starting from Astellas AS2444697 (<strong>1a</strong>). The work includes identification of the pyrazole-pyridine substituent in compound <strong>1</strong><strong>g</strong>, binding towards the gatekeeper region of IRAK4, followed by a structure-guided scaffold hybridization that led to <strong>5a</strong>. Subsequent optimization of substituents of the indazole scaffold yielded <strong>5e</strong>, which exhibits a 10-fold improvement in IRAK4 cell potency and higher off-target selectivity compared to AS244697 (<strong>1a</strong>).</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"131 ","pages":"Article 118333"},"PeriodicalIF":3.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145090791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modular helix stabilization via alkenyl butylcarbamate staples: effects of staple length, stereochemistry, and directionality","authors":"Ha T.N. Nguyen ,&nbsp;Thanh K. Pham ,&nbsp;Young-Woo Kim","doi":"10.1016/j.bmc.2025.118334","DOIUrl":"10.1016/j.bmc.2025.118334","url":null,"abstract":"<div><div>Peptide stapling is a widely used approach for stabilizing α-helical peptides, improving their structural integrity, proteolytic resistance, and therapeutic potential. Here, we present a novel stapling strategy employing alkenyl butylcarbamate cross-links formed via ring-closing metathesis (RCM). This platform enables fine control over staple length, stereochemistry, and directionality. Through systematic analysis, the 13-atom hex-2-enyl butylcarbamate staple was identified as optimal, achieving enhanced α-helicity and efficient macrocyclization. We further demonstrate that peptide stereochemistry and staple orientation significantly impact both RCM efficiency and helix stabilization. Notably, the optimized stapled peptides exhibited a 45-fold increase in resistance to trypsin-mediated degradation compared to their unmodified counterparts. In addition, the carbamate linkage provided excellent resistance to non-enzymatic hydrolysis under physiological conditions. Together, these results highlight alkenyl butylcarbamate stapling as a chemically robust, hydrophilic, and conformationally rigid approach for stabilizing α-helical peptides. This strategy offers an attractive alternative to traditional hydrocarbon staples, particularly for therapeutic peptides targeting extracellular or membrane-bound proteins</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"129 ","pages":"Article 118334"},"PeriodicalIF":3.0,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144722161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}