Pathogenic protozoan parasites such as Plasmodium spp. (malaria) and Leishmania spp. (leishmaniasis) have a huge negative impact on human health across the globe. One common feature of these parasites is membrane-bound pyrophosphatases (mPPases), which couple the hydrolysis of pyrophosphate to pumping of H⁺/Na⁺ ions and consequently generate an electrochemical potential across the acidocalcisomal membrane.¹ Albeit this essential role for many pathogenic protozoan parasites, mPPases do not exist in humans and could thus serve as promising drug targets. So far, the therapeutic utility has been limited and only few non-phosphorus inhibitors of mPPases inhibitors have been reported.²

Our aim is to develop organic mPPase inhibitors capable of disrupting this key ion gradient of pathogenic protozoan parasites in order to decrease their viability. Here, we present the exploration of an isoxazole fragment hit and the discovery of small mPPase inhibitors with 6–10 µM IC₅₀ values in our test system (Thermotoga maritima).³ Furthermore, these inhibitors retained their activity against Plasmodium falciparum mPPase in membranes.

1. Shah, R. N.; Vidilaseris, K.; Xhaard, H.; Goldman, A. AIMS Biophysics 2016, 3 (1), 171–194. DOI: 10.3934/biophy.2016.1.171
2. Vidilaseris, K.; Kiriazis, A.; Turku, A.; Khattab, A.; Johansson, N. G.; Leino, T. O.; Kiuru, P. S.; Boije af Gennäs, G.; Meri, S.; Yli-Kauhaluoma, J.; Xhaard, H.; Goldman, A. Science Advances 2019, 5 (5), eaav7575. DOI: 10.1126/sciadv.aav7574
3. Johansson, N. G.; Turku, A.; Vidilaseris, K.; Dreano, L.; Khattab, A.; Ayuso Pérez, D.; Wilkinson, A.; Zhang, Y.; Tamminen, M.; Grazhdankin, E.; Kiriazis, A.; Fishwick, C. W. G.; Meri, S.; Yli-Kauhaluoma, J.; Goldman, A.; Boije af Gennäs, G.; Xhaard, H. ACS Med. Chem. Lett. 2020, 11 (4), 605–610. DOI: 10.1021/acsmedchemlett.9b00537

Matti Tamminen

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