دورية أكاديمية
أعرض في EDS

The Trypanosoma cruzi TcrNT2 Nucleoside Transporter Is a Conduit for the Uptake of 5-F-2'-Deoxyuridine and Tubercidin Analogues.

التفاصيل البيبلوغرافية
العنوان: The Trypanosoma cruzi TcrNT2 Nucleoside Transporter Is a Conduit for the Uptake of 5-F-2'-Deoxyuridine and Tubercidin Analogues.
المؤلفون: Aldfer MM; School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK., Alfayez IA; School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK., Elati HAA; School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK., Gayen N; School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK., Elmahallawy EK; School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.; Department of Zoonoses, Faculty of Veterinary Medicine, Sohag University, Sohag 82524, Egypt., Milena Murillo A; Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil., Marsiccobetre S; Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil., Van Calenbergh S; Laboratory for Medicinal Chemistry (Campus Heymans), Ghent University, B-9000 Gent, Belgium., Silber AM; Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil., de Koning HP; School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.
المصدر: Molecules (Basel, Switzerland) [Molecules] 2022 Nov 19; Vol. 27 (22). Date of Electronic Publication: 2022 Nov 19.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI, c1995-
مواضيع طبية MeSH: Trypanosoma cruzi* , Chagas Disease*/drug therapy, Humans ; Nucleoside Transport Proteins ; Tubercidin ; Biological Transport ; Deoxyuridine
مستخلص: Among the scarce validated drug targets against Chagas disease (CD), caused by Trypanosoma cruzi , the parasite's nucleoside salvage system has recently attracted considerable attention. Although the trypanocidal activity of tubercidin (7-deazapurine) has long been known, the identification of a class of 7-substituted tubercidin analogs with potent in vitro and in vivo activity and much-enhanced selectivity has made nucleoside analogs among the most promising lead compounds against CD. Here, we investigate the recently identified TcrNT2 nucleoside transporter and its potential role in antimetabolite chemotherapy. TcrNT2, expressed in a Leishmania mexicana cell line lacking the NT1 nucleoside transporter locus, displayed very high selectivity and affinity for thymidine with a K m of 0.26 ± 0.05 µM. The selectivity was explained by interactions of 2-oxo, 4-oxo, 5-Me, 3'-hydroxy and 5'-hydroxy with the transporter binding pocket, whereas a hydroxy group at the 2' position was deleterious to binding. This made 5-halogenated 2'-deoxyuridine analogues good substrates but 5-F-2'-deoxyuridine displayed disappointing activity against T. cruzi trypomastigotes. By comparing the EC 50 values of tubercidin and its 7-substituted analogues against L. mexicana Cas9, Cas9 ΔNT1 and Cas9 ΔNT1+TcrNT2 it was shown that TcrNT2 can take up tubercidin and, at a minimum, a subset of the analogs.
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معلومات مُعتمدة: Studentships to M.A.A. and H.A..A.E. Covernment of Libya; MR/P027989/1 United Kingdom MRC_ Medical Research Council; Newton Research Travel Grant Royal Society; Daniel Turnberg Fellowship United Kingdom AMS_ Academy of Medical Sciences; studentship to I.A.A. Saudi Arabia Ministry of Health
فهرسة مساهمة: Keywords: 5-F-2′-deoxyuridine; TcrNT2; Trypanosoma cruzi; antimetabolite; nucleoside transporter; pyrimidine transporter; thymidine; tubercidin analog
المشرفين على المادة: 0 (Nucleoside Transport Proteins)
M351LCX45Y (Tubercidin)
W78I7AY22C (Deoxyuridine)
تواريخ الأحداث: Date Created: 20221126 Date Completed: 20221129 Latest Revision: 20230222
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC9693223
DOI: 10.3390/molecules27228045
PMID: 36432150
قاعدة البيانات: MEDLINE
الوصف
تدمد:1420-3049
DOI:10.3390/molecules27228045