دورية أكاديمية
An Optimized Dihydrodibenzothiazepine Lead Compound (SBI-0797750) as a Potent and Selective Inhibitor of Plasmodium falciparum and P. vivax Glucose 6-Phosphate Dehydrogenase 6-Phosphogluconolactonase.
| العنوان: | An Optimized Dihydrodibenzothiazepine Lead Compound (SBI-0797750) as a Potent and Selective Inhibitor of Plasmodium falciparum and P. vivax Glucose 6-Phosphate Dehydrogenase 6-Phosphogluconolactonase. |
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| المؤلفون: | Berneburg I; Justus Liebig University Giessen, Biochemistry and Molecular Biology, Interdisciplinary Research Center, Giessen, Germany., Peddibhotla S; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA., Heimsch KC; Justus Liebig University Giessen, Biochemistry and Molecular Biology, Interdisciplinary Research Center, Giessen, Germany., Haeussler K; Justus Liebig University Giessen, Biochemistry and Molecular Biology, Interdisciplinary Research Center, Giessen, Germany.; University of California, San Diegogrid.266100.3, La Jolla, California, USA., Maloney P; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA., Gosalia P; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA., Preuss J; Justus Liebig University Giessen, Biochemistry and Molecular Biology, Interdisciplinary Research Center, Giessen, Germany.; University of California, San Diegogrid.266100.3, La Jolla, California, USA., Rahbari M; Justus Liebig University Giessen, Biochemistry and Molecular Biology, Interdisciplinary Research Center, Giessen, Germany., Skorokhod O; Department of Life Sciences and Systems Biology, University of Torino, Turin, Italy., Valente E; Department of Oncology, University of Torino, Turin, Italy., Ulliers D; Department of Oncology, University of Torino, Turin, Italy., Simula LF; Department of Clinical Chemistry, Ospedale Civile, Alghero, Italy., Buchholz K; Justus Liebig University Giessen, Biochemistry and Molecular Biology, Interdisciplinary Research Center, Giessen, Germany., Hedrick MP; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA., Hershberger P; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA., Chung TDY; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA., Jackson MR; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA., Schwarzer E; Department of Oncology, University of Torino, Turin, Italy., Rahlfs S; Justus Liebig University Giessen, Biochemistry and Molecular Biology, Interdisciplinary Research Center, Giessen, Germany., Bode L; University of California, San Diegogrid.266100.3, La Jolla, California, USA., Becker K; Justus Liebig University Giessen, Biochemistry and Molecular Biology, Interdisciplinary Research Center, Giessen, Germany., Pinkerton AB; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA. |
| المصدر: | Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2022 Apr 19; Vol. 66 (4), pp. e0210921. Date of Electronic Publication: 2022 Mar 10. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 0315061 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-6596 (Electronic) Linking ISSN: 00664804 NLM ISO Abbreviation: Antimicrob Agents Chemother Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, American Society for Microbiology |
| مواضيع طبية MeSH: | Antimalarials*/pharmacology , Antimalarials*/therapeutic use , Glucosephosphate Dehydrogenase Deficiency* , Malaria* , Malaria, Falciparum*/drug therapy , Malaria, Vivax*/drug therapy, Carboxylic Ester Hydrolases ; Glucose/metabolism ; Glucosephosphate Dehydrogenase/metabolism ; Humans ; Hydrogen Peroxide/metabolism ; Phosphates ; Plasmodium falciparum/metabolism ; Plasmodium vivax |
| مستخلص: | In Plasmodium , the first two and rate-limiting enzymes of the pentose phosphate pathway, glucose 6-phosphate dehydrogenase (G6PD) and the 6-phosphogluconolactonase, are bifunctionally fused to a unique enzyme named GluPho, differing structurally and mechanistically from the respective human orthologs. Consistent with the enzyme's essentiality for malaria parasite proliferation and propagation, human G6PD deficiency has immense impact on protection against severe malaria, making Pf GluPho an attractive antimalarial drug target. Herein we report on the optimized lead compound N -(((2R,4S)-1-cyclobutyl-4-hydroxypyrrolidin-2-yl)methyl)-6-fluoro-4-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide (SBI-0797750), a potent and fully selective Pf GluPho inhibitor with robust nanomolar activity against recombinant Pf GluPho, Pv G6PD, and P. falciparum blood-stage parasites. Mode-of-action studies have confirmed that SBI-0797750 disturbs the cytosolic glutathione-dependent redox potential, as well as the cytosolic and mitochondrial H |
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| معلومات مُعتمدة: | R01 AI104916 United States AI NIAID NIH HHS; U54 HG005033 United States HG NHGRI NIH HHS |
| فهرسة مساهمة: | Keywords: G6PDH; Plasmodium; Plasmodium falciparum; Plasmodium vivax; inhibitors; malaria |
| المشرفين على المادة: | 0 (Antimalarials) 0 (Phosphates) BBX060AN9V (Hydrogen Peroxide) EC 1.1.1.49 (Glucosephosphate Dehydrogenase) EC 3.1.1.- (Carboxylic Ester Hydrolases) EC 3.1.1.31 (6-phosphogluconolactonase) IY9XDZ35W2 (Glucose) |
| تواريخ الأحداث: | Date Created: 20220310 Date Completed: 20220421 Latest Revision: 20220911 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC9017341 |
| DOI: | 10.1128/aac.02109-21 |
| PMID: | 35266827 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1098-6596 |
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| DOI: | 10.1128/aac.02109-21 |