Authors

H Alkhalaf¹; HP De Koning¹; A Hofer²;  ¹ University of Glasgow , UK;  ² University of Umea, Sweden

Discussion

One of the main barriers between the identification of potential lead compounds against parasite-borne diseases and their clinical development as potential new drugs is that the development cost for a possible drug against a single neglected disease is deemed to be too high relative to the potential benefits for the manufacturer. Adenosine analogues with potent activity against veterinary trypanosomiasis have been identified [1–3], but most are much less active against Leishmania species. We reasoned that the most likely reasons for the uneven activity were (a) differences in activation by adenosine kinase (AK) or (b) differences in adenosine transporters, which are NT1 in Leishmania and P1 and P2/TbAT1 in Trypanosoma brucei brucei [2,4]. We have created a number of investigative cell lines, including L. mexicana ΔLmexAK, and ΔLmexAK expressing TbbAK to investigate whether Leishmania AK could be the factor limiting sensitivity to adenosine analogues. Equally, we created ΔLmexNT1 (null adenosine uptake) and T. brucei ΔTbAT1 as well as ΔLmexNT1 expressing T. congolense and T. vivax P1-type adenosine transporters. The SAR of the AKs were investigated by determining the EC50 values for adenosine analogues against the various cell lines, transporters and AKs. Docking studies were conducted comparing the poses of analogues in the Leishmania and Trypanosoma adenosine kinases. Detailed transport assays of nucleoside analogues as inhibitors of LmexNT1 are being conducted.
[1] Mabille, D. et al., 2022. Int J Parasitol Drugs Drug Resist. 19, 21–30 [2] Ungogo, M.A. et al., 2023. Int J Mol Sci. 24, 3144. [3] Ilbeigi, K. et al., 2025. ACS Infect Dis. 11, 131–143 [4] Aldfer, M.M. et al., 2022. Int J Mol Sci. 23, 8139