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

• DOI: 10.3390/molecules27228045
• Publication Date: 2022-11-21T09:33:32Z
• Authors: Mustafa M. Aldfer; Ibrahim A. Alfayez; Hamza A. A. Elati; Nilanjana Gayen; Ehab Kotb Elmahal...; Ana Milena Murillo; Sabrina Marsiccob...; Serge Van Calenbergh; Ariel M. Silber; Harry P. de Koning
• Keywords: Deoxyuridine

Among the scarce validated drug targets against Chagas disease (CD), caused by Trypanosoma cruzi, parasite's nucleoside salvage system has recently attracted considerable attention. Although trypanocidal activity of tubercidin (7-deazapurine) long been known, identification a class 7-substituted analogs with potent in vitro and vivo much-enhanced selectivity made among most promising lead compounds CD. Here, we investigate identified TcrNT2 transporter its potential role antimetabolite chemotherapy. TcrNT2, expressed Leishmania mexicana cell line lacking NT1 locus, displayed very high affinity for thymidine Km 0.26 ± 0.05 µM. The was explained interactions 2-oxo, 4-oxo, 5-Me, 3'-hydroxy 5'-hydroxy binding pocket, whereas hydroxy group at 2' position deleterious to binding. This 5-halogenated 2'-deoxyuridine analogues good substrates but 5-F-2'-deoxyuridine disappointing T. cruzi trypomastigotes. By comparing EC50 values L. Cas9, Cas9ΔNT1 Cas9ΔNT1+TcrNT2 it shown that can take up and, minimum, subset analogs.