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

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 clas...

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Autores principales: Aldfer, Mustafa M., Alfayez, Ibrahim A., Elati, Hamza A. A., Gayen, Nilanjana, Elmahallawy, Ehab Kotb, Milena Murillo, Ana, Marsiccobetre, Sabrina, Van Calenbergh, Serge, Silber, Ariel M., de Koning, Harry P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9693223/
https://www.ncbi.nlm.nih.gov/pubmed/36432150
http://dx.doi.org/10.3390/molecules27228045
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author Aldfer, Mustafa M.
Alfayez, Ibrahim A.
Elati, Hamza A. A.
Gayen, Nilanjana
Elmahallawy, Ehab Kotb
Milena Murillo, Ana
Marsiccobetre, Sabrina
Van Calenbergh, Serge
Silber, Ariel M.
de Koning, Harry P.
author_facet Aldfer, Mustafa M.
Alfayez, Ibrahim A.
Elati, Hamza A. A.
Gayen, Nilanjana
Elmahallawy, Ehab Kotb
Milena Murillo, Ana
Marsiccobetre, Sabrina
Van Calenbergh, Serge
Silber, Ariel M.
de Koning, Harry P.
author_sort Aldfer, Mustafa M.
collection PubMed
description 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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spelling pubmed-96932232022-11-26 The Trypanosoma cruzi TcrNT2 Nucleoside Transporter Is a Conduit for the Uptake of 5-F-2′-Deoxyuridine and Tubercidin Analogues Aldfer, Mustafa M. Alfayez, Ibrahim A. Elati, Hamza A. A. Gayen, Nilanjana Elmahallawy, Ehab Kotb Milena Murillo, Ana Marsiccobetre, Sabrina Van Calenbergh, Serge Silber, Ariel M. de Koning, Harry P. Molecules Article 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. MDPI 2022-11-19 /pmc/articles/PMC9693223/ /pubmed/36432150 http://dx.doi.org/10.3390/molecules27228045 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Aldfer, Mustafa M.
Alfayez, Ibrahim A.
Elati, Hamza A. A.
Gayen, Nilanjana
Elmahallawy, Ehab Kotb
Milena Murillo, Ana
Marsiccobetre, Sabrina
Van Calenbergh, Serge
Silber, Ariel M.
de Koning, Harry P.
The Trypanosoma cruzi TcrNT2 Nucleoside Transporter Is a Conduit for the Uptake of 5-F-2′-Deoxyuridine and Tubercidin Analogues
title The Trypanosoma cruzi TcrNT2 Nucleoside Transporter Is a Conduit for the Uptake of 5-F-2′-Deoxyuridine and Tubercidin Analogues
title_full The Trypanosoma cruzi TcrNT2 Nucleoside Transporter Is a Conduit for the Uptake of 5-F-2′-Deoxyuridine and Tubercidin Analogues
title_fullStr The Trypanosoma cruzi TcrNT2 Nucleoside Transporter Is a Conduit for the Uptake of 5-F-2′-Deoxyuridine and Tubercidin Analogues
title_full_unstemmed The Trypanosoma cruzi TcrNT2 Nucleoside Transporter Is a Conduit for the Uptake of 5-F-2′-Deoxyuridine and Tubercidin Analogues
title_short The Trypanosoma cruzi TcrNT2 Nucleoside Transporter Is a Conduit for the Uptake of 5-F-2′-Deoxyuridine and Tubercidin Analogues
title_sort trypanosoma cruzi tcrnt2 nucleoside transporter is a conduit for the uptake of 5-f-2′-deoxyuridine and tubercidin analogues
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9693223/
https://www.ncbi.nlm.nih.gov/pubmed/36432150
http://dx.doi.org/10.3390/molecules27228045
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