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Evaluation of the Leishmania Inositol Phosphorylceramide Synthase as a Drug Target Using a Chemical and Genetic Approach.

التفاصيل البيبلوغرافية
العنوان: Evaluation of the Leishmania Inositol Phosphorylceramide Synthase as a Drug Target Using a Chemical and Genetic Approach.
المؤلفون: Alpizar-Sosa EA; Department of Biosciences, University of Durham, South Road, Durham, DH1 3LE, U.K., Zimbres FM; Department of Biosciences, University of Durham, South Road, Durham, DH1 3LE, U.K., Mantilla BS; Department of Biosciences, University of Durham, South Road, Durham, DH1 3LE, U.K., Dickie EA; School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, U.K., Wei W; Department of Biosciences, University of Durham, South Road, Durham, DH1 3LE, U.K., Burle-Caldas GA; Department of Biosciences, University of Durham, South Road, Durham, DH1 3LE, U.K.; Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Caixa Postal 486 31270-901, Belo Horizonte, Minas Gerais, Brazil., Filipe LNS; Department of Biosciences, University of Durham, South Road, Durham, DH1 3LE, U.K., Van Bocxlaer K; York Biomedical Research Institute, Hull York Medical School, University of York, York YO10 5NG, U.K., Price HP; School of Life Sciences, Keele University, Staffordshire, ST5 5BG, U.K., Ibarra-Meneses AV; Département de Pathologie et Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Quebec J2S 2M2, Canada., Beaudry F; Département de Biomédecine, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Quebec J2S 2M2, Canada., Fernandez-Prada C; Département de Pathologie et Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Quebec J2S 2M2, Canada., Whitfield PD; School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, U.K., Barrett MP; School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, U.K., Denny PW; Department of Biosciences, University of Durham, South Road, Durham, DH1 3LE, U.K.
المصدر: ACS infectious diseases [ACS Infect Dis] 2024 Aug 09; Vol. 10 (8), pp. 2913-2928. Date of Electronic Publication: 2024 Jul 18.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: ACS Publications Country of Publication: United States NLM ID: 101654580 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2373-8227 (Electronic) Linking ISSN: 23738227 NLM ISO Abbreviation: ACS Infect Dis Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : ACS Publications, [2015]-
مواضيع طبية MeSH: Antiprotozoal Agents*/pharmacology , Antiprotozoal Agents*/chemistry, Sphingolipids/metabolism ; Hexosyltransferases/genetics ; Hexosyltransferases/metabolism ; Hexosyltransferases/antagonists & inhibitors ; Leishmania/drug effects ; Leishmania/genetics ; Leishmania/enzymology ; Animals ; Leishmania mexicana/drug effects ; Leishmania mexicana/genetics ; Leishmania mexicana/enzymology ; Glycosphingolipids/metabolism ; Transferases (Other Substituted Phosphate Groups)/genetics ; Transferases (Other Substituted Phosphate Groups)/metabolism
مستخلص: The lack of effective vaccines and the development of resistance to the current treatments highlight the urgent need for new anti-leishmanials. Sphingolipid metabolism has been proposed as a promising source of Leishmania -specific targets as these lipids are key structural components of the eukaryotic plasma membrane and are involved in distinct cellular events. Inositol phosphorylceramide (IPC) is the primary sphingolipid in the Leishmania species and is the product of a reaction mediated by IPC synthase (IPCS). The antihistamine clemastine fumarate has been identified as an inhibitor of IPCS in L. major and a potent anti-leishmanial in vivo . Here we sought to further examine the target of this compound in the more tractable species L. mexicana , using an approach combining genomic, proteomic, metabolomic and lipidomic technologies, with molecular and biochemical studies. While the data demonstrated that the response to clemastine fumarate was largely conserved, unexpected disturbances beyond sphingolipid metabolism were identified. Furthermore, while deletion of the gene encoding Lmx IPCS had little impact in vitro , it did influence clemastine fumarate efficacy and, importantly, in vivo pathogenicity. Together, these data demonstrate that clemastine does inhibit Lmx IPCS and cause associated metabolic disturbances, but its primary target may lie elsewhere.
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فهرسة مساهمة: Keywords: CRISPR-Cas9; Leishmania; clemastine fumarate; inositol phosphorylceramide synthase; polyomics; thermal proteomic profiling
المشرفين على المادة: 0 (Antiprotozoal Agents)
0 (Sphingolipids)
EC 2.4.1.- (Hexosyltransferases)
EC 2.4.1.- (phosphatidylinositol-ceramide phosphoinositol transferase)
0 (inositolphosphorylceramide)
0 (Glycosphingolipids)
EC 2.7.8.- (Transferases (Other Substituted Phosphate Groups))
تواريخ الأحداث: Date Created: 20240718 Date Completed: 20240809 Latest Revision: 20240815
رمز التحديث: 20240815
مُعرف محوري في PubMed: PMC11320567
DOI: 10.1021/acsinfecdis.4c00284
PMID: 39023360
قاعدة البيانات: MEDLINE
الوصف
تدمد:2373-8227
DOI:10.1021/acsinfecdis.4c00284