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Development of 2-Methyl-5-phenylpyrrolidine-Based ST2 Inhibitors for Neuroinflammatory Conditions 基于2-甲基-5-苯基吡咯烷的ST2神经炎症抑制剂的开发
IF 3.9 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-27 DOI: 10.1021/acsmedchemlett.6c00349
Xinrui Yuan, Eun Bee Cho, Amol D. Patil, Md. Aktaruzzaman, Andhavaram Ramaraju, Chenyao Jiang, Meilin Wang, Miao He, Aaron Robida, Bo Wen, Duxin Sun, Jason C. Rech, Jianxiong Jiang, Chao-Yie Yang
{"title":"Development of 2-Methyl-5-phenylpyrrolidine-Based ST2 Inhibitors for Neuroinflammatory Conditions","authors":"Xinrui Yuan,&nbsp;Eun Bee Cho,&nbsp;Amol D. Patil,&nbsp;Md. Aktaruzzaman,&nbsp;Andhavaram Ramaraju,&nbsp;Chenyao Jiang,&nbsp;Meilin Wang,&nbsp;Miao He,&nbsp;Aaron Robida,&nbsp;Bo Wen,&nbsp;Duxin Sun,&nbsp;Jason C. Rech,&nbsp;Jianxiong Jiang,&nbsp;Chao-Yie Yang","doi":"10.1021/acsmedchemlett.6c00349","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00349","url":null,"abstract":"<p>The cytokine receptor,ST2, is expressed in immune cellsincludingtype 2 T cells, microglia, and astrocytes. ST2 binds with IL-33 toactivate the downstream NF-κB pathway. Besides the role of theST2/IL-33 axis in the expansion of type 2 and regulatory T cells,it mediates the production of pro-inflammatory cytokines by a subsetof myeloid cells under inflammatory conditions. Here, we designedand synthesized a new series of ST2 inhibitors by modifying the pyrrolidinecore in our previous lead to develop <strong>XY-280</strong>. Our assessmentindicated that <strong>XY-280</strong> is the first ST2 inhibitor demonstratingfavorable brain-penetration properties, making it a suitable toolfor CNS-targeted studies. In the LPS-induced neuroinflammation models, <strong>XY-280</strong> significantly attenuated disease-associated pro-inflammatorycytokines (IL-1β, IL-6, TNF-α) and prostaglandin E2 productionin both <em>in vitro</em> and <em>in vivo</em> systems.These findings identify <strong>XY-280</strong> as a promising candidatefor the ST2 inhibitor development to treat disorders associated withneuroinflammation.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1915–1922"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729841","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}
引用次数: 0
Peptidic Phosphonates as Irreversible Covalent Inhibitors of Plasmodium falciparum Serine Protease PfSUB1 肽膦酸盐作为恶性疟原虫丝氨酸蛋白酶PfSUB1的不可逆共价抑制剂
IF 3.9 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-19 DOI: 10.1021/acsmedchemlett.6c00268
Armands Kazia, Elina Lidumniece, Chrislaine Withers-Martinez, Liva Eglite, Owain Donnelly, David A. Fidock, Michael J. Blackman, Aigars Jirgensons
{"title":"Peptidic Phosphonates as Irreversible Covalent Inhibitors of Plasmodium falciparum Serine Protease PfSUB1","authors":"Armands Kazia,&nbsp;Elina Lidumniece,&nbsp;Chrislaine Withers-Martinez,&nbsp;Liva Eglite,&nbsp;Owain Donnelly,&nbsp;David A. Fidock,&nbsp;Michael J. Blackman,&nbsp;Aigars Jirgensons","doi":"10.1021/acsmedchemlett.6c00268","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00268","url":null,"abstract":"<p>Malaria, caused by <em>Plasmodium</em> parasites,remainsa major global health challenge, exacerbated by the widespread emergenceof drug-resistant plasmodium strains. Subtilisin-like serine proteaseSUB1 triggers escape of the parasite from the red cell via a processcalled egress, rendering the enzyme a prospective antimalarial drugtarget. While several SUB1 inhibitors have been developed, irreversiblecovalent inhibition has not been explored so far. In this work, wereport our studies of peptidic inhibitors bearing covalent serinetraps such as β-lactam, β-lactone, epoxide, and diarylphosphonate. Out of these, peptidic diaryl phosphonates were foundto be irreversible PfSUB1 inhibitors, with the best inhibitor <strong>3b</strong> showing a PfSUB1 inhibitory potency (IC<sub>50</sub>) of167 nM.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1873–1877"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729595","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}
引用次数: 0
Advancing Next-Generation Psychedelic Therapeutics through Selective 5-HT2A Activation, Precision Aerosol Delivery, and Optimized 5-MeO-DMT Treatment Paradigms 通过选择性5-HT2A激活，精确气溶胶输送和优化的5-MeO-DMT治疗范式推进下一代迷幻治疗
IF 3.9 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-10 DOI: 10.1021/acsmedchemlett.6c00364
Anna C. Renner, Robert B. Kargbo
{"title":"Advancing Next-Generation Psychedelic Therapeutics through Selective 5-HT2A Activation, Precision Aerosol Delivery, and Optimized 5-MeO-DMT Treatment Paradigms","authors":"Anna C. Renner,&nbsp;Robert B. Kargbo","doi":"10.1021/acsmedchemlett.6c00364","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00364","url":null,"abstract":"<p>The psychedelic therapeutics field continues to evolvebeyond classicalhallucinogens toward integrated treatment platforms that combine optimizedpharmacology, drug delivery, and clinical implementation. Recent patentapplications disclose selective 5-HT2A receptor activators, precisionaerosol delivery technologies for psychedelic compounds, and structured5-MeO-DMT treatment regimens for depression. Together, these innovationsillustrate a convergence toward scalable, safer, and clinically practicalneuropsychiatric therapies that may reshape the future of serotonergicmedicine.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1707–1709"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148718497","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}
引用次数: 0
Understanding the Photodynamic Behavior of Red Emitting Re(I)dipyrrinates in Triple-Negative Breast Cancer Cells 了解三阴性乳腺癌细胞中红色发射Re(I)二吡啶酸酯的光动力学行为
IF 3.9 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-31 DOI: 10.1021/acsmedchemlett.6c00168
Neha Manav, Jaydeepsinh Chavda, Dhiraj Bhatia, Iti Gupta
{"title":"Understanding the Photodynamic Behavior of Red Emitting Re(I)dipyrrinates in Triple-Negative Breast Cancer Cells","authors":"Neha Manav,&nbsp;Jaydeepsinh Chavda,&nbsp;Dhiraj Bhatia,&nbsp;Iti Gupta","doi":"10.1021/acsmedchemlett.6c00168","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00168","url":null,"abstract":"<p>The Re(I)dipyrrinates complexes having oligo ethyleneglycol (OEG)and thioglucose/thiogalactose sugars at the C-8 position are exploredfor anticancer applications. The X-ray crystal structure of Re(I)dipyrrinatehaving a thiogalactose sugar revealed distorted octrahedral geometryof the central metal. The Re(I)dipyrrinates showed red emission (600–900nm) with noticeably large Stokes shifts (∼5890–6800cm<sup>–1</sup>), a highly desirable property for bioimagingapplication. The Re(I)dipyrrinates were found to be nontoxic in darkconditions on triple negative breast cancer cells (TNBC), whereasRe(I)dipyrrinate with OEG group and thioglucose sugar displayed excellentphototoxicity in TNBC with IC<sub>50</sub> values of 2.6 and 1.5 μM,respectively. The Re(I)dipyrrinate with OEG group displayed preferentialcolocalization in the lipid droplets and caused lipid peroxidationafter light exposure. Additionally, all Re(I)dipyrrinates were nontoxicto the normal retinal pigment epithelial cells (RPE-1) both in thedark and under light irradiation, reflecting suitable behavior asthe anticancer agents for photodynamic therapy.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1780–1786"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148718562","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}
引用次数: 0
Nicotinamide-Based Covalent Inhibitors of tRNA (m1G37) Methyltransferase (TrmD) to Increase Antibacterial Activity 基于烟酰胺的tRNA （m1G37）甲基转移酶（TrmD）共价抑制剂提高抗菌活性
IF 3.9 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-06-10 DOI: 10.1021/acsmedchemlett.6c00164
Isao Masuda, Simon D. P. Baugh, Kevin McClay, Ryan J. Ford, Lily Tayag, Eric D. Strobel, Thomas Grant, Samantha A. DeSando, Hongjuan Guo, Thomas Christian, Diana Bao Hang, Zheng Ruan, John L. Kulp, III, Katie B. Freeman, Ya-Ming Hou, Allen B. Reitz, Dipti Kanabar
{"title":"Nicotinamide-Based Covalent Inhibitors of tRNA (m1G37) Methyltransferase (TrmD) to Increase Antibacterial Activity","authors":"Isao Masuda,&nbsp;Simon D. P. Baugh,&nbsp;Kevin McClay,&nbsp;Ryan J. Ford,&nbsp;Lily Tayag,&nbsp;Eric D. Strobel,&nbsp;Thomas Grant,&nbsp;Samantha A. DeSando,&nbsp;Hongjuan Guo,&nbsp;Thomas Christian,&nbsp;Diana Bao Hang,&nbsp;Zheng Ruan,&nbsp;John L. Kulp, III,&nbsp;Katie B. Freeman,&nbsp;Ya-Ming Hou,&nbsp;Allen B. Reitz,&nbsp;Dipti Kanabar","doi":"10.1021/acsmedchemlett.6c00164","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00164","url":null,"abstract":"<p>Bacterial tRNA (m<sup>1</sup>G37) methyltransferase (TrmD)is anessential enzyme required for accurate translation and representsan attractive antibacterial target distinct from its eukaryotic counterpart,Trm5. Here, we describe the development of nicotinamide-based TrmDinhibitors incorporating electrophilic Michael-acceptor motifs toenhance cellular antibacterial activity. Mass spectrometry-based peptidemapping shows covalent modification of TrmD at Cys112, a residue proximalto the AdoMet (<em>S</em>-adenosylmethionine) binding region,providing a mechanistic basis for covalent target engagement. Consistentwith this mechanism, electrophile-containing analogues showed improvedantibacterial activity compared with the parent scaffold. In bacterialgrowth inhibition assays, selected compounds displayed greater functionalspecificity for TrmD-driven growth suppression relative to human Trm5,supporting preferential bacterial target engagement. Collectively,these results establish Cys112 as a chemically addressable site forcovalent inhibition of TrmD and provide a foundation for the developmentof TrmD-directed antibacterial agents.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1766–1779"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148718493","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}
引用次数: 0
Neutrophil Elastase-Responsive Linkers for Precision Antibody–Drug Conjugates 用于精确抗体-药物偶联物的中性粒细胞弹性酶反应连接物
IF 3.9 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-14 DOI: 10.1021/acsmedchemlett.6c00363
Anna C. Renner, Robert B. Kargbo
{"title":"Neutrophil Elastase-Responsive Linkers for Precision Antibody–Drug Conjugates","authors":"Anna C. Renner,&nbsp;Robert B. Kargbo","doi":"10.1021/acsmedchemlett.6c00363","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00363","url":null,"abstract":"<p>Antibody–drug conjugates (ADCs) continue to transform oncology,yet premature payload release remains a major source of toxicity.This invention describes a novel class of neutrophil elastase-responsivelinker systems that incorporate β-homoamino acids, α-methylaminoacids, and polyethylene glycol motifs to improve plasma stabilitywhile enabling selective drug release at disease sites. These linkertechnologies offer a versatile platform for enhancing ADC efficacy,safety, and therapeutic precision.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1710–1713"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148718501","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}
引用次数: 0
Antischistosomal Ozonide Glycine Ethyl Esters 抗血吸虫臭氧甘氨酸乙酯
IF 3.9 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-24 DOI: 10.1021/acsmedchemlett.6c00330
Rongguo Ren, Cécile Häberli, Gong Chen, Sandeep K. Singh, Kailey M. Bruha, Paul H. Davis, Yuxiang Dong, Susan A. Charman, Jennifer Keiser, Jonathan L. Vennerstrom
{"title":"Antischistosomal Ozonide Glycine Ethyl Esters","authors":"Rongguo Ren,&nbsp;Cécile Häberli,&nbsp;Gong Chen,&nbsp;Sandeep K. Singh,&nbsp;Kailey M. Bruha,&nbsp;Paul H. Davis,&nbsp;Yuxiang Dong,&nbsp;Susan A. Charman,&nbsp;Jennifer Keiser,&nbsp;Jonathan L. Vennerstrom","doi":"10.1021/acsmedchemlett.6c00330","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00330","url":null,"abstract":"<p>Building on the discoverythat synthetic ozonides have not onlyantimalarial but also antischistosomal properties, we now report thesynthesis and antischistosomal activity of a series of ozonide glycineethyl esters. We identified ozonide glycine zwitterion <strong>19</strong> and its ethyl ester <strong>17</strong> as new antischistosomal leadcompounds. Ozonides <strong>17</strong> and <strong>19</strong> had high invivo antischistosomal activity against adult worms and low cytotoxicity.Based on <em>C</em><sub>max</sub> and AUC<sub>0–24 h</sub> values, exposure of <strong>19</strong> after administration of itsethyl ester <strong>17</strong> was approximately 1.5-fold higher thanthat observed after dosing <strong>19</strong> itself.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1909–1914"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148718506","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}
引用次数: 0
Synthetic Diastereomers of the Fungal Cycloheptapeptide Paraisariamide A Retain Ternatin-Like Biological Activity 真菌环七肽副伞虫酰胺A非对映体的合成
IF 3.9 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-01 DOI: 10.1021/acsmedchemlett.6c00180
Sophia E. Bonar, Daphne R. Mattos, Takumi Arai, Yui Tagami, Dean A. Buch, Richard M. Tehan, Kerry L. McPhail, Shinya Oishi, Jane E. Ishmael
{"title":"Synthetic Diastereomers of the Fungal Cycloheptapeptide Paraisariamide A Retain Ternatin-Like Biological Activity","authors":"Sophia E. Bonar,&nbsp;Daphne R. Mattos,&nbsp;Takumi Arai,&nbsp;Yui Tagami,&nbsp;Dean A. Buch,&nbsp;Richard M. Tehan,&nbsp;Kerry L. McPhail,&nbsp;Shinya Oishi,&nbsp;Jane E. Ishmael","doi":"10.1021/acsmedchemlett.6c00180","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00180","url":null,"abstract":"<p>Paraisariamides (Psds) are a family of fungal N-methylatedcyclicheptapeptides with structural similarity to the translation eukaryoticelongation factor 1A inhibitor ternatin. Initial characterizationof the eight known Psds A–H revealed a complex biological activityprofile; Psd A and Psds E–H showed differential cytotoxicityto HCT116 colon cancer cells, whereas Psds B–D were inactive.Here, we report that Psd A is a weak inhibitor of total protein synthesisand that three synthetic diastereomers of Psd A retain comparablepharmacological activity. Psd A and all structural variants decreasedthe level of expression of extracellular <em>Gaussia</em> luciferase in a phenotypic assay that senses endoplasmic reticulumstress in living cells. Inhibition of cellular secretion was fullyreversible; however, the three Psd A diastereomers were all eventuallycytotoxic to HCT116 colon cancer cells. The stereochemistry of PsdA, a weak cytotoxin relative to Psds E–H, is anticipated toinform future structure–activity relationship studies of theseternatin-like molecules.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1787–1794"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729408","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}
引用次数: 0
Novel Compounds as Orexin 2 Receptor Agonists for Treating Narcolepsy 新化合物作为食欲素2受体激动剂治疗发作性睡病
IF 3.9 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-09 DOI: 10.1021/acsmedchemlett.6c00342
Ram W. Sabnis, Anika R. Sabnis
{"title":"Novel Compounds as Orexin 2 Receptor Agonists for Treating Narcolepsy","authors":"Ram W. Sabnis,&nbsp;Anika R. Sabnis","doi":"10.1021/acsmedchemlett.6c00342","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00342","url":null,"abstract":"<p>Provided herein are novel compoundsas orexin 2 receptoragonists,pharmaceutical compositions, use of such compounds in treating narcolepsy,and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 8","pages":"1699–1700"},"PeriodicalIF":3.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729670","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}
引用次数: 0
Design and Synthesis of Phosphonoproline-Proline Bioisosteric Mimetics of Proline Dimers: Pseudopeptide Constructs as Potential Inhibitors of the Zn-Metalloprotease PPEP-1 Associated with Clostridioides difficile 脯氨酸二聚体的磷酸脯氨酸-脯氨酸生物等构模拟物的设计和合成：与艰难梭菌相关的锌金属蛋白酶PPEP-1的潜在抑制剂的假肽构建物
IF 3.9 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2026-07-09 Epub Date: 2026-06-11 DOI: 10.1021/acsmedchemlett.6c00221
Erick Ivan Martinez Toto, Sofiane Hocine, Jean-Baptiste Garsi, Paul Skrzypczak, Elena Brunstein, Ulrich Baumann* and Stephen Hanessian*, 
{"title":"Design and Synthesis of Phosphonoproline-Proline Bioisosteric Mimetics of Proline Dimers: Pseudopeptide Constructs as Potential Inhibitors of the Zn-Metalloprotease PPEP-1 Associated with Clostridioides difficile","authors":"Erick Ivan Martinez Toto,&nbsp;Sofiane Hocine,&nbsp;Jean-Baptiste Garsi,&nbsp;Paul Skrzypczak,&nbsp;Elena Brunstein,&nbsp;Ulrich Baumann* and Stephen Hanessian*,&nbsp;","doi":"10.1021/acsmedchemlett.6c00221","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00221","url":null,"abstract":"<p >The design, synthesis and preliminary inhibitory activity of novel phosphonoproline–proline-containing pseudohexapeptides against PPEP-1, a metalloprotease secreted by <i>Clostridioides difficile</i>, is reported. Remarkably, the P<sub>(<i>R</i>)</sub>-configured phosphonoproline–proline hexapeptide bioisostere of the synthetic heptapeptide Ac-EVNPPVP-NH<sub>2</sub> is 1000 times more active than the corresponding P<sub>(<i>S</i>)</sub> analogue as measured by a FRET assay, which represents a binding energy of about 12 kJ/mol. Placing an embedded enantiopure phosphonoproline unit to replace a proline within a peptidic construct constitutes a promising venue in the design of proline-containing metalloenzyme inhibitors.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 7","pages":"1629–1635"},"PeriodicalIF":3.9,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409351","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}
引用次数: 0
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