Studies of the membrane-bound pyrophosphatase as a potential drug target against protist parasites

Tue19  Oct02:45pm(30 mins)
Where:
Room 3A
Dr Keni Vidilaseris

Abstract

Protist parasite diseases, such as malaria, toxoplasmosis, and leishmaniasis, cause tremendous problems worldwide and have enormous health, social and economic impacts. All these parasites have membrane-bound pyrophosphatases (mPPases), enzymes that couple the hydrolysis or synthesis of pyrophosphate to proton and/or sodium active transport across membranes. mPPases are also important for the growth of protist parasites causing disease. Because of their absence in animals and humans, the enzyme represents a potential candidate for rational drug design against those parasites. Here we present the development of mPPase inhibitors and their activities against bacterial (Thermotoga maritima) and protist (Plasmodium falciparum) mPPases to low micromolar inhibitory activities. Further testing of the promising inhibitors in the P. falciparum survival assay in erythrocytes showed that some compounds were able to inhibit the parasite growth; with the best one, mPP-0293, have the IC50 of 3.6 µM. We also solved the complex structure of the bacterial mPPase from T. maritima with ATC, the first non-phosphorous mPPase inhibitor, by X-ray crystallography. The compound binds as a dimer to a hitherto-unknown allosteric site near the enzyme exit channel, creating a hydrophobic clamp that prevents the hydrophobic gate from opening. Altogether, the complex structure opens a new route to drug discovery of parasitic diseases by targeting mPPase at its allosteric binding site.

Keywords: membrane-bound pyrophosphatase, X-ray crystallography, inhibitor, drug design

Reference:
1. Shah, N.R., Vidilaseris, K., Xhaard, H. and Goldman, A., 2016. Integral membrane pyrophosphatases: a novel drug target for human pathogens?. AIMS Biophysics, 3(1), pp.171-194.
2. Vidilaseris, K., Kiriazis, A., Turku, A., Khattab, A., Johansson, N.G., Leino, T.O., Kiuru, P.S., af Gennäs, G.B., Meri, S., Yli-Kauhaluoma, J. and Xhaard, H., 2019. Asymmetry in catalysis by Thermotoga maritima membrane-bound pyrophosphatase demonstrated by a nonphosphorus allosteric inhibitor. Science advances, 5(5), p.eaav7574.
3. Johansson, N.G., Turku, A., Vidilaseris, K., Dreano, L., Khattab, A., Ayuso Pérez, D., Wilkinson, A., Zhang, Y., Tamminen, M., Grazhdankin, E. and Kiriazis, A., 2020. Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment. ACS medicinal chemistry letters, 11(4), pp.605-610.

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