Journal of Medicinal Chemistry最新文献_第4页

gem -Dimethylcarbinol: A tert -Butyl Bioisostere with Greatly Reduced Lipophilicity gem -二甲基甲醇：一种亲脂性大大降低的叔丁基生物等异构体

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-18 DOI: 10.1021/acs.jmedchem.6c02769

Debora Chiodi,Yoshihiro Ishihara

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Discovery of Epoxysuccinates as Potent Covalent Inhibitors of SARS-CoV-2 Papain-like Protease 环氧琥珀酸酯作为SARS-CoV-2木瓜蛋白酶有效共价抑制剂的发现

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-18 DOI: 10.1021/acs.jmedchem.6c01914

Farinaz Soleymani,Ganga Reddy Velma,Zhengnan Shen,Cameron Holberg,Jiqiang Fu,Divakar Reddy Indukuri,Soumya Reddy Musku,Elizaveta Lazarova,Steve Slilaty,Zuomei Li,Kiira Ratia,Rui Xiong,Gregory R. J. Thatcher

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Cascade Mono- and Di-Functionalization of Anticancer Diastereomeric Benzoxazole-Ansamycins toward the Development of Highly Potent Hsp90 Inhibitors of Decreased Toxicity in Normal Cells 抗肿瘤非对映异构体苯并恶唑-安霉素级联单和双功能化，以开发高效的Hsp90抑制剂，降低正常细胞的毒性

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-18 DOI: 10.1021/acs.jmedchem.6c00563

Aleksandra Leśniewska,Adam Buczkowski,Piotr Ruszkowski,Matthew J. Binder,Alison D. Axtman,Wojciech Schilf,Ewelina Smolarz,Krystian Pyta,Maria Gdaniec,Franz J. Bartl,Piotr Przybylski

{"title":"Cascade Mono- and Di-Functionalization of Anticancer Diastereomeric Benzoxazole-Ansamycins toward the Development of Highly Potent Hsp90 Inhibitors of Decreased Toxicity in Normal Cells","authors":"Aleksandra Leśniewska,Adam Buczkowski,Piotr Ruszkowski,Matthew J. Binder,Alison D. Axtman,Wojciech Schilf,Ewelina Smolarz,Krystian Pyta,Maria Gdaniec,Franz J. Bartl,Piotr Przybylski","doi":"10.1021/acs.jmedchem.6c00563","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c00563","url":null,"abstract":"To reduce toxicity of geldanamycin (GDM), the domino transformation of its benzoquinone core into benzoxazole has been performed. Structural studies of ester-phenol and ester-ether benzoxazole-type ansamycins indicate that the former is present as (Sp)-diastereomer, whereas the latter is present as conformation-“locked” (Rp)-diastereomer, which is more favorable at binding to Hsp90. Several of the obtained benzoxazole ansamycins revealed high anticancer potency in SKBr-3, MCF-7, SKOV-3, and PC-3 lines with improved selectivity and lower affinity to glutathione, compared to GDM. The most potent derivative 6 reveals excellent anticancer activity (IC50 < 0.6 μM) with Hsp90 as the primary target [KD6-Hsp90 = 0.3 μM], limited off-target effects (kinases), and decreased toxicity (selectivity indices = 2.75−3.48) regarding GDM. Ester-ether type derivative 22 reveals good anticancer potency in SKOV-3 (IC50 = 0.62 μM) with reduced toxicity in human dermal fibroblast and human umbilical vein endothelial cells, improved selectivity (SISKOV-3 = 2.75), apoptotic index AISKOV-3 ∼8, and high chemical and in vivo stabilities.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"42 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Dual Peptide Modification via Isopeptide Bonding and Lipidation Boosts Antifungal Activity 双肽修饰通过异肽结合和脂化增强抗真菌活性

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-17 DOI: 10.1021/acs.jmedchem.6c01856

Daniel Ben Hur,Naiem Ahmad Wani,Elad Stolovicki,Monika Kluzek,Jakub Abramson,Yechiel Shai

{"title":"Dual Peptide Modification via Isopeptide Bonding and Lipidation Boosts Antifungal Activity","authors":"Daniel Ben Hur,Naiem Ahmad Wani,Elad Stolovicki,Monika Kluzek,Jakub Abramson,Yechiel Shai","doi":"10.1021/acs.jmedchem.6c01856","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01856","url":null,"abstract":"Abstract The rapid rise in drug-resistant infectious diseases urgently demands new therapeutic strategies, particularly against fungi. Antimicrobial peptides (AMPs) are key effectors of innate immunity in all organisms, killing various microorganisms. Despite their potential, few AMPs effectively target pathogens without harming the host. Here, we incorporated isopeptide bonds and lipophilic acids into AMPs, forming lipo-isopeptides (LIIPs). LIIPs were active against diverse microorganisms, predominantly Candida albicans (C. albicans), and exhibited improved protease resistance. These modifications altered the secondary structure and oligomerization behavior, while enhancing membrane affinity. Consequently, by coating surfaces and cells, the non-toxic C8-Amp1EP reduces fungal adhesion and biofilm formation, and acts by disrupting and depolarizing the C. albicans membrane at both planktonic and biofilm stages. Importantly, under serial-passage conditions, C8-Amp1EP showed a lower propensity to induce resistance than conventional antifungal treatments. These findings identify LIIPs as promising, selective agents for combating infections, paving the way for future therapeutic development.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"30 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Design, Synthesis and Dual-Stage Antimalarial Evaluation of β-Carboline−Metronidazole Hybrids: Structure−Activity Relationship and Molecular Docking Correlations β-卡波林-甲硝唑杂合体的设计、合成及双阶段抗疟评价：构效关系和分子对接关系

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-17 DOI: 10.1021/acs.jmedchem.6c02225

Alka Raj Pandey,Suriya Pratap Singh,Rohini Nandi,Shabeer Ali H,Rama Krishna Rayiti,Shovan Ghosh,Gokul Krishnan Nagendran,Sathish Kumar Mudedla,Rabi Sankar Bhatta,Satish Mishra,Koneni V. Sashidhara

{"title":"Design, Synthesis and Dual-Stage Antimalarial Evaluation of β-Carboline−Metronidazole Hybrids: Structure−Activity Relationship and Molecular Docking Correlations","authors":"Alka Raj Pandey,Suriya Pratap Singh,Rohini Nandi,Shabeer Ali H,Rama Krishna Rayiti,Shovan Ghosh,Gokul Krishnan Nagendran,Sathish Kumar Mudedla,Rabi Sankar Bhatta,Satish Mishra,Koneni V. Sashidhara","doi":"10.1021/acs.jmedchem.6c02225","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02225","url":null,"abstract":"Abstract Malaria remains a major global health challenge, exacerbated by emerging drug-resistant Plasmodium strains. Herein, we report the design, synthesis, and dual-stage antimalarial evaluation of β-carboline−metronidazole hybrids. The synthesized hybrids, linked through ester and amide bonds, were evaluated in vitro against chloroquine-sensitive (Pf3D7) and resistant (PfK1) Plasmodium falciparum strains, as well as liver-stage Plasmodium berghei. Several compounds exhibited potent blood-stage inhibition (IC50 as low as 0.05 ± 0.02 μM), remarkable liver-stage activity surpassing primaquine, and favourable selectivity indices (&gt;100). Notably, compound 8kkk achieved up to 95% suppression of parasitemia in P. berghei ANKA-infected Swiss mice at 50 mg/kg for four days. Pharmacokinetic studies revealed a distinct absorption and disposition profile. SAR analysis highlighted the importance of electronic nature and substitution pattern of the β-carboline scaffold, while molecular docking and fluorimetry analysis indicated strong binding to PfLDH. These findings suggest β-carboline−metronidazole hybrids as promising candidates for further development as dual-stage antimalarial agents.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"37 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Enhancing the Specificity of the CAIX-Targeted Radionuclide Probe via the Optimization Cyclic Peptide Cyclization Linker 优化环肽环化连接体增强caix靶向放射性核素探针的特异性

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-17 DOI: 10.1021/acs.jmedchem.6c02281

Fuhai Wu,Zhen Chen,Huan Chen,Yu Xing,Zhiyuan Liu,Xingye Lin,Guanzhe Wang,Dongchen Han,Shanshan Qiu,Zhenyuan Zhang,Yan Chen,Yunhao Ren,Zhixin Wu,Dongfang Xia,Kai Cao,Xuhu Huang,Hongyu Li,Xueyun Gao

{"title":"Enhancing the Specificity of the CAIX-Targeted Radionuclide Probe via the Optimization Cyclic Peptide Cyclization Linker","authors":"Fuhai Wu,Zhen Chen,Huan Chen,Yu Xing,Zhiyuan Liu,Xingye Lin,Guanzhe Wang,Dongchen Han,Shanshan Qiu,Zhenyuan Zhang,Yan Chen,Yunhao Ren,Zhixin Wu,Dongfang Xia,Kai Cao,Xuhu Huang,Hongyu Li,Xueyun Gao","doi":"10.1021/acs.jmedchem.6c02281","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02281","url":null,"abstract":"Abstract Carbonic anhydrase IX (CAIX) is a key biomarker for clear cell renal cell carcinoma (ccRCC) PET imaging. The reported probe 68Ga-DPI-4452 strongly targets both hCAIX and hCAII, therefore hindering its clinical applications. This study developed two optimized probes, 68Ga-WF1 and 68Ga-WF2. They have nanomolar affinity for hCAIX but far weaker binding to hCAII compared with that of 68Ga-DPI-4452. In OS-RC-2 tumor-bearing mice, the tumor uptake of 68Ga-WF1 and 68Ga-WF2 was comparable to that of 68Ga-DPI-4452. However, since 68Ga-WF2 exhibited the lowest affinity for mCAII and mCAIX, its gastrointestinal uptake was the lowest. The autoradiography result revealed that three probes strongly bound human ccRCC tissues, while 68Ga-WF1 and 68Ga-WF2 bound far less to digestive tract tissues. Due to the lowest affinity of 68Ga-WF1 for hCAII, it effectively reduces uptake in the human gastrointestinal tract, holding promise for high tumor contrast and low gastrointestinal tract toxicity for ccRCC PET imaging.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"12 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Discovery of Potent, Orally Bioavailable, and CNS-Penetrant 1,2,3-Triazolopyridinyl Piperazine-Based PARP1-Selective Inhibitors 基于1,2,3-三唑吡啶基哌嗪的有效、口服生物有效、cns渗透的parp1选择性抑制剂的发现

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-17 DOI: 10.1021/acs.jmedchem.6c01265

Tammy Ladduwahetty,Benjamin F. Rahemtulla,Eric P. A. Talbot,Joseph Bateman,Neil Benson,Pengyuan Chen,Xiao-Ling Cockcroft,Li Feng,Elnaz Gozalpour,Kui Lin,Mustafa Moroglu,Yi Qin,Emily Raoshan,Joseline Ratnam,Yang Shen,Steve Sollis,Zixuan Tong,Tingzhong Wang,Marta Westwood,Yiming Xie,Siew Kuen Yeap,Rui Yuan,Gillian F. Watt,Simon Taylor,Kevin M. Foote

{"title":"Discovery of Potent, Orally Bioavailable, and CNS-Penetrant 1,2,3-Triazolopyridinyl Piperazine-Based PARP1-Selective Inhibitors","authors":"Tammy Ladduwahetty,Benjamin F. Rahemtulla,Eric P. A. Talbot,Joseph Bateman,Neil Benson,Pengyuan Chen,Xiao-Ling Cockcroft,Li Feng,Elnaz Gozalpour,Kui Lin,Mustafa Moroglu,Yi Qin,Emily Raoshan,Joseline Ratnam,Yang Shen,Steve Sollis,Zixuan Tong,Tingzhong Wang,Marta Westwood,Yiming Xie,Siew Kuen Yeap,Rui Yuan,Gillian F. Watt,Simon Taylor,Kevin M. Foote","doi":"10.1021/acs.jmedchem.6c01265","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01265","url":null,"abstract":"Abstract Hematological toxicities have resulted in limiting the dose of first-generation PARP inhibitors, which have activity at both PARP1 and PARP2. With the advancement of selective PARP1 inhibitors to the clinic, we embarked on a program to identify novel PARP1 inhibitors that are suitable for the treatment of CNS malignancies. Central to our design was the replacement of the carboxamide in saruparib with a series of heterocycles. Our progression criteria included using Caco-2 efflux instead of the more commonly used MDR1-MDCK efflux to enable identifying compounds with Kpu,u &gt;0.3. This work culminated in the discovery of the potent, selective, orally bioavailable, and CNS-penetrant PARP1 inhibitor 33, which demonstrated tumor growth inhibition and regression in xenograft models at 0.2 mg/kg QD. Predicted human PK parameters coupled with a tumor growth PKPD model for 33 estimated an efficacious clinical dose of &lt;150 mg once daily.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"413 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Exploring the Relationship between Cell Permeability, Intracellular Exposure, and Target Engagement for PROTACs 探索细胞通透性、细胞内暴露和PROTACs靶接合之间的关系

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-17 DOI: 10.1021/acs.jmedchem.6c02063

Emma Inganäs,Bomi Jung,Constanze Hilgendorf,Pär Matsson

{"title":"Exploring the Relationship between Cell Permeability, Intracellular Exposure, and Target Engagement for PROTACs","authors":"Emma Inganäs,Bomi Jung,Constanze Hilgendorf,Pär Matsson","doi":"10.1021/acs.jmedchem.6c02063","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02063","url":null,"abstract":"Abstract Proteolysis-targeting chimeras (PROTACs) occupy beyond-rule-of-5 chemical space, where cellular activity depends on molecular recognition, membrane permeation and unbound exposure at the target site. Here, we examined how these properties shape apparent E3 ligase target engagement for 20 PROTACs spanning different E3 ligase ligands, linkers, and target-binding ligands. Intracellular NanoBRET assays showed a wide range of IC50 values for competition with cereblon or VHL tracer binding when referenced to externally applied concentrations. Passive Caco-2 permeability related only weakly to these values. Recalculating IC50 values using measured intracellular unbound exposure narrowed the spread from approximately 4000-fold to 150-fold, in quantitative agreement with IC50 values measured directly in permeabilized cells. Thus, much of the apparent variation in target engagement reflects differential intracellular exposure rather than intrinsic E3 ligase recognition, and incorporating unbound exposure provides a more mechanistic basis for interpreting cellular target engagement data and distinguishing exposure-driven effects from genuine structure−activity relationships.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"22 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Development of Long-Acting Teriparatide Analogues through Iterative Peptide Scanning and Site-Specific Modification by Serine/Threonine Ligation 通过迭代肽扫描和丝氨酸/苏氨酸连接的位点特异性修饰开发长效特立帕肽类似物

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-16 DOI: 10.1021/acs.jmedchem.6c01924

Biyao Liu,Kaixuan Song,Hongli Sui,Zhuang Li,Huarong Shao,Fei Liu,Kang Jin

{"title":"Development of Long-Acting Teriparatide Analogues through Iterative Peptide Scanning and Site-Specific Modification by Serine/Threonine Ligation","authors":"Biyao Liu,Kaixuan Song,Hongli Sui,Zhuang Li,Huarong Shao,Fei Liu,Kang Jin","doi":"10.1021/acs.jmedchem.6c01924","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01924","url":null,"abstract":"Abstract Teriparatide, the only FDA-approved osteoanabolic drug for osteoporosis, suffers from poor metabolic stability and requires frequent subcutaneous injections, leading to suboptimal patient compliance. To find optimized teriparatide derivatives, we herein report an iterative peptide scanning strategy followed by a serine/threonine ligation (STL) chemistry for site-specific modifications. Using our 2-hydroxyphenol-pseudoproline (ψ2-hydroxyphenolpro) modification (HPM) method, two series of teriparatide analogues with different types of substituents were successfully prepared for scanning the modifiable sites and their expansibility. Through chemoselective acylation of embedded serine/threonine residues, several fatty acids of unequal lengths were introduced to further improve the pharmacokinetic properties of scanning derivatives. Among the 12 lipidated analogues, 54, 55, 62, and 63 exhibited potent antiosteoporotic activities in vitro and in vivo close to those of native teriparatide. The most effective compound, 62, also demonstrated significantly enhanced serum stability and may serve as a promising candidate for further development of long-acting antiosteoporotic pharmaceuticals.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"21 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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A Novel Chemotype of Orally Active SARS-CoV-2 NSP14 Methyltransferase Inhibitors 一种新型口服活性SARS-CoV-2 NSP14甲基转移酶抑制剂的化学型

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2026-10-16 DOI: 10.1021/acs.jmedchem.6c01763

Cindy Meyer,Aitor Garzia,James R. Merritt,Joel S. Freundlich,Hans-Heinrich Hoffmann,Alison W. Ashbrook,Matthew Zimmerman,Andrew M. Nelson,Jada A. Davis,James M. Balkovec,Madhuvika Murugan,Ching-Wen Chang,Neelam Oswal,Suyapa Penalva-Lopez,Vijeta Sharma,Enriko Dolgov,Julianna Cangialosi,Pankaj Sharma,Julius Nitsche,Oleg Ganichkin,Stefan Steinbacher,J. Fraser Glickman,Charles M. Rice,David S. Perlin,Thomas Tuschl

{"title":"A Novel Chemotype of Orally Active SARS-CoV-2 NSP14 Methyltransferase Inhibitors","authors":"Cindy Meyer,Aitor Garzia,James R. Merritt,Joel S. Freundlich,Hans-Heinrich Hoffmann,Alison W. Ashbrook,Matthew Zimmerman,Andrew M. Nelson,Jada A. Davis,James M. Balkovec,Madhuvika Murugan,Ching-Wen Chang,Neelam Oswal,Suyapa Penalva-Lopez,Vijeta Sharma,Enriko Dolgov,Julianna Cangialosi,Pankaj Sharma,Julius Nitsche,Oleg Ganichkin,Stefan Steinbacher,J. Fraser Glickman,Charles M. Rice,David S. Perlin,Thomas Tuschl","doi":"10.1021/acs.jmedchem.6c01763","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01763","url":null,"abstract":"Abstract The periodic emergence of human coronaviruses (hCoVs) necessitates direct-acting antivirals targeting underexploited viral proteins with broad-spectrum potential. Building on our discovery of TDI-015051, a first-in-class SARS-CoV-2 mRNA cap guanine-N7 methyltransferase (MTase) NSP14 inhibitor whose translational development was limited by metabolic liabilities, we conducted medicinal chemistry optimization of a structurally distinct high-throughput screening hit. We arrived at MAVDA-K-256, a small-molecule inhibitor with improved pharmacological properties compared to TDI-015051. MAVDA-K-256 engaged NSP14 through the formation of a ternary complex with S-adenosyl-l-homocysteine, potently inhibiting its MTase activity and SARS-CoV-2 replication (EC50 = 24.6 nM). MAVDA-K-256 demonstrated broad-spectrum antiviral activity against diverse hCoVs without targeting the host mRNA cap MTase. Its favorable metabolic stability and pharmacokinetic properties enabled twice-daily oral dosing in a murine SARS-CoV-2 infection model, resulting in a five-log reduction in viral lung burden. These findings validate NSP14 inhibition as a promising antiviral strategy and support further preclinical development of MAVDA-K-256.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"71 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0