ACS Medicinal Chemistry Letters最新文献_第9页

Cyclic Peptide C5aR1 Antagonist Design Using Solution Conformational Analysis Derived from Residual Dipolar Couplings 利用残余双极偶联的溶液构象分析设计环肽 C5aR1 拮抗剂

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-10-29 DOI: 10.1021/acsmedchemlett.4c0031610.1021/acsmedchemlett.4c00316

Kathleen A. Farley*, Ye Che, Ricardo Lira, Peter Jones, Nikolaos Papaioannou, Matthew Hayward, Mark E. Flanagan, Jonathan Langille, Sidney Liang, Betsy S. Pierce, Gregory Ciszewski, Paul Bonin, Fabien Vincent, Simeon Ramsey and David Hepworth,

{"title":"Cyclic Peptide C5aR1 Antagonist Design Using Solution Conformational Analysis Derived from Residual Dipolar Couplings","authors":"Kathleen A. Farley*, Ye Che, Ricardo Lira, Peter Jones, Nikolaos Papaioannou, Matthew Hayward, Mark E. Flanagan, Jonathan Langille, Sidney Liang, Betsy S. Pierce, Gregory Ciszewski, Paul Bonin, Fabien Vincent, Simeon Ramsey and David Hepworth, ","doi":"10.1021/acsmedchemlett.4c0031610.1021/acsmedchemlett.4c00316","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00316https://doi.org/10.1021/acsmedchemlett.4c00316","url":null,"abstract":"To gain further insight into the conformational properties of small cyclic peptides that bind to the G-protein coupled receptor C5aR1, we report here for the first time the elucidation of three peptide solution conformations using residual dipolar couplings and NMR temperature coefficients. Each of these peptides varies by at least one amino acid, adopts a different intramolecular hydrogen bonding pattern, and has a different solution conformation. The solution conformations were used in combination with a homology structure of C5aR1 as a design template for increasing the potency of peptide leads for the C5a receptor. This study provides a framework for using RDC solution conformations to guide the design of peptide mimetics that emulate the target bound state in solution to minimize the strain energy of the bound conformation and improve potency of the peptide for the target.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 11","pages":"2060–2066 2060–2066"},"PeriodicalIF":3.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142641076","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

Bicyclic Ureas as JAK2 Inhibitors for Treating Hematological Cancer 双环脲类作为 JAK2 抑制剂治疗血液肿瘤

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-10-29 DOI: 10.1021/acsmedchemlett.4c0049610.1021/acsmedchemlett.4c00496

Ram W. Sabnis*,

引用次数: 0

Cyclic Peptide C5aR1 Antagonist Design Using Solution Conformational Analysis Derived from Residual Dipolar Couplings. 利用残余双极偶联的溶液构象分析设计环肽 C5aR1 拮抗剂

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-10-29 eCollection Date: 2024-11-14 DOI: 10.1021/acsmedchemlett.4c00316

Kathleen A Farley, Ye Che, Ricardo Lira, Peter Jones, Nikolaos Papaioannou, Matthew Hayward, Mark E Flanagan, Jonathan Langille, Sidney Liang, Betsy S Pierce, Gregory Ciszewski, Paul Bonin, Fabien Vincent, Simeon Ramsey, David Hepworth

{"title":"Cyclic Peptide C5aR1 Antagonist Design Using Solution Conformational Analysis Derived from Residual Dipolar Couplings.","authors":"Kathleen A Farley, Ye Che, Ricardo Lira, Peter Jones, Nikolaos Papaioannou, Matthew Hayward, Mark E Flanagan, Jonathan Langille, Sidney Liang, Betsy S Pierce, Gregory Ciszewski, Paul Bonin, Fabien Vincent, Simeon Ramsey, David Hepworth","doi":"10.1021/acsmedchemlett.4c00316","DOIUrl":"10.1021/acsmedchemlett.4c00316","url":null,"abstract":"To gain further insight into the conformational properties of small cyclic peptides that bind to the G-protein coupled receptor C5aR1, we report here for the first time the elucidation of three peptide solution conformations using residual dipolar couplings and NMR temperature coefficients. Each of these peptides varies by at least one amino acid, adopts a different intramolecular hydrogen bonding pattern, and has a different solution conformation. The solution conformations were used in combination with a homology structure of C5aR1 as a design template for increasing the potency of peptide leads for the C5a receptor. This study provides a framework for using RDC solution conformations to guide the design of peptide mimetics that emulate the target bound state in solution to minimize the strain energy of the bound conformation and improve potency of the peptide for the target.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 11","pages":"2060-2066"},"PeriodicalIF":3.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Optimization of a Piperidine CD4-Mimetic Scaffold Sensitizing HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity 优化哌啶 CD4 拟态支架，使 HIV-1 感染细胞对抗体依赖性细胞毒性敏感

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-10-28 DOI: 10.1021/acsmedchemlett.4c0040310.1021/acsmedchemlett.4c00403

Daniel Lee, Ling Niu, Shilei Ding, Huile Zhu, William D. Tolbert, Halima Medjahed, Guillaume Beaudoin-Bussières, Cameron Abrams, Andrés Finzi*, Marzena Pazgier* and Amos B. Smith III*,

{"title":"Optimization of a Piperidine CD4-Mimetic Scaffold Sensitizing HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity","authors":"Daniel Lee, Ling Niu, Shilei Ding, Huile Zhu, William D. Tolbert, Halima Medjahed, Guillaume Beaudoin-Bussières, Cameron Abrams, Andrés Finzi*, Marzena Pazgier* and Amos B. Smith III*, ","doi":"10.1021/acsmedchemlett.4c0040310.1021/acsmedchemlett.4c00403","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00403https://doi.org/10.1021/acsmedchemlett.4c00403","url":null,"abstract":"The ability of the HIV-1 accessory proteins Nef and Vpu to decrease CD4 protects infected cells from antibody-dependent cellular cytotoxicity (ADCC) by limiting the exposure of vulnerable epitopes to envelope glycoprotein (Env). Small-molecule CD4 mimetics (CD4mcs) based on piperidine scaffolds represent a new family of agents capable of sensitizing HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes on Env that are recognized by non-neutralizing antibodies which are abundant in plasma of people living with HIV. Here, we employed the combined methods of parallel synthesis, structure-based design, and optimization to generate a new line of piperidine-based CD4mcs, which sensitize HIV-1 infected cells to ADCC activity. The X-ray crystallographic study of the CD4mcs within the gp120 residues suggests that the positioning of the CD4mc inside the Phe43 cavity and synergistic contact of the CD4mc with the β20–21 loop and the α1-helix lead to improved antiviral activity.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 11","pages":"1961–1969 1961–1969"},"PeriodicalIF":3.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142641010","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

Optimization of a Piperidine CD4-Mimetic Scaffold Sensitizing HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity. 优化哌啶CD4模拟支架，使HIV-1感染细胞对抗体依赖性细胞毒性敏感

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-10-28 eCollection Date: 2024-11-14 DOI: 10.1021/acsmedchemlett.4c00403

Daniel Lee, Ling Niu, Shilei Ding, Huile Zhu, William D Tolbert, Halima Medjahed, Guillaume Beaudoin-Bussières, Cameron Abrams, Andrés Finzi, Marzena Pazgier, Amos B Smith

{"title":"Optimization of a Piperidine CD4-Mimetic Scaffold Sensitizing HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity.","authors":"Daniel Lee, Ling Niu, Shilei Ding, Huile Zhu, William D Tolbert, Halima Medjahed, Guillaume Beaudoin-Bussières, Cameron Abrams, Andrés Finzi, Marzena Pazgier, Amos B Smith","doi":"10.1021/acsmedchemlett.4c00403","DOIUrl":"10.1021/acsmedchemlett.4c00403","url":null,"abstract":"The ability of the HIV-1 accessory proteins Nef and Vpu to decrease CD4 protects infected cells from antibody-dependent cellular cytotoxicity (ADCC) by limiting the exposure of vulnerable epitopes to envelope glycoprotein (Env). Small-molecule CD4 mimetics (CD4mcs) based on piperidine scaffolds represent a new family of agents capable of sensitizing HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes on Env that are recognized by non-neutralizing antibodies which are abundant in plasma of people living with HIV. Here, we employed the combined methods of parallel synthesis, structure-based design, and optimization to generate a new line of piperidine-based CD4mcs, which sensitize HIV-1 infected cells to ADCC activity. The X-ray crystallographic study of the CD4mcs within the gp120 residues suggests that the positioning of the CD4mc inside the Phe43 cavity and synergistic contact of the CD4mc with the β20-21 loop and the α1-helix lead to improved antiviral activity.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 11","pages":"1961-1969"},"PeriodicalIF":3.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Toward Dual Targeting of Catalytic and Gatekeeper Pockets in Cyclophilins Using a Macrocyclic Scaffold 利用大环支架实现嗜环蛋白催化和守门口袋的双重靶向定位

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-10-28 DOI: 10.1021/acsmedchemlett.4c0042710.1021/acsmedchemlett.4c00427

Johannes K. Dreizler, Christian Meyners and Felix Hausch*,

引用次数: 0

Development of BODIPY FL SNS 032 as a Versatile Probe for Constitutive Androstane Receptor and Multiple Kinases 将 BODIPY FL SNS 032 开发为一种多功能探针，用于检测组成型雄甾烷受体和多种激酶

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-10-28 DOI: 10.1021/acsmedchemlett.4c0041610.1021/acsmedchemlett.4c00416

Wenwei Lin, and , Taosheng Chen*,

{"title":"Development of BODIPY FL SNS 032 as a Versatile Probe for Constitutive Androstane Receptor and Multiple Kinases","authors":"Wenwei Lin,  and , Taosheng Chen*, ","doi":"10.1021/acsmedchemlett.4c0041610.1021/acsmedchemlett.4c00416","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00416https://doi.org/10.1021/acsmedchemlett.4c00416","url":null,"abstract":"Human constitutive androstane receptor (hCAR) regulates xenobiotic metabolism. Its large and flexible ligand binding pocket can accommodate structurally diverse compounds. An assay for characterizing the binding of ligands to hCAR is needed but has not been reported. Here, we first discovered the promiscuous kinase inhibitor SNS-032 and its derivative THAL-SNS-032 as binders of hCAR, then developed BODIPY FL SNS 032 (14) as a high-affinity hCAR fluorescent probe (Kd: 300 ± 30 nM) in a TR-FRET binding assay and used it to characterize hCAR ligands for their competitive binding activities. BODIPY FL SNS 032 also displayed high binding affinities to multiple kinases, such as hGSK3A (Kd: 4.5 ± 0.2 nM), hCDK9/CycT1 (Kd: 5.1 ± 0.6 nM), hMAPK15 (Kd: 340 ± 20 nM), hCASK (Kd: 550 ± 30 nM), and hCAMKK2 (Kd: 530 ± 40 nM). BODIPY FL SNS 032 is therefore a versatile probe for hCAR and multiple kinases.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 11","pages":"1987–1996 1987–1996"},"PeriodicalIF":3.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640926","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

Bicyclic Inhibitors of Branched-Chain α-Keto Acid Dehydrogenase Kinase (BDK) with In Vivo Activity 具有体内活性的支链α-酮酸脱氢酶激酶（BDK）双环抑制剂

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-10-28 DOI: 10.1021/acsmedchemlett.4c0036210.1021/acsmedchemlett.4c00362

Jue Liang, Xiaoyu Wang, Francisco Ortiz, Gauri Shishodia, Tian Liu, Chen Gao, Noelle S. Williams, David T. Chuang, R. Max Wynn and Joseph M. Ready*,

引用次数: 0

Bicyclic Inhibitors of Branched-Chain α-Keto Acid Dehydrogenase Kinase (BDK) with In Vivo Activity. 具有体内活性的支链α-酮酸脱氢酶激酶（BDK）双环抑制剂。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-10-28 eCollection Date: 2024-11-14 DOI: 10.1021/acsmedchemlett.4c00362

Jue Liang, Xiaoyu Wang, Francisco Ortiz, Gauri Shishodia, Tian Liu, Chen Gao, Noelle S Williams, David T Chuang, R Max Wynn, Joseph M Ready

引用次数: 0

Development of BODIPY FL SNS 032 as a Versatile Probe for Constitutive Androstane Receptor and Multiple Kinases. 将 BODIPY FL SNS 032 开发为一种多功能探针，用于检测组成型雄甾烷受体和多种激酶。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-10-28 eCollection Date: 2024-11-14 DOI: 10.1021/acsmedchemlett.4c00416

Wenwei Lin, Taosheng Chen

引用次数: 0