Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment.

Niklas G Johansson,Keni Vidilaseris,Alexandros Kiriazis,Matti Tamminen,Colin W G Fishwick,Aaron Wilkinson,Daniel Ayuso Pérez,Seppo Meri,Ainoleena Turku,Yuezhou Zhang,Evgeni Grazhdankin,Jari Yli-Kauhaluoma,Loïc Dreano,Gustav Boije Af Gennäs,Henri Xhaard,Adrian Goldman,Ayman Khattab

doi:10.1021/acsmedchemlett.9b00537

Niklas G Johansson, Keni Vidilaseris + Show 15 more

Open Access

https://doi.org/10.1021/acsmedchemlett.9b00537

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Abstract

Membrane-bound pyrophosphatases (mPPases) regulate energy homeostasis in pathogenic protozoan parasites and lack human homologues, which makes them promising targets in e.g. malaria. Yet only few nonphosphorus inhibitors have been reported so far. Here, we explore an isoxazole fragment hit, leading to the discovery of small mPPase inhibitors with 6–10 μM IC50 values in the Thermotoga maritima test system. Promisingly, the compounds retained activity against Plasmodium falciparum mPPase in membranes and inhibited parasite growth.

Highlights

Membrane-bound pyrophosphatases regulate energy homeostasis in pathogenic protozoan parasites and lack human homologues, which makes them promising targets in e.g. malaria
Protozoan diseases such as malaria and leishmaniasis affect many vertebrate species and are a major cause of human mortality or morbidity worldwide.[1,2]. They are caused by protist parasites such as Plasmodium spp., Toxoplasma spp., Trypanosoma spp., and Leishmania spp
Parasitic protists express one or two types of membranebound pyrophosphatases, which are the focus of this study.[10,11] Membrane-bound pyrophosphatases (mPPases) are large (70−81 kDa) homodimeric integral membrane proteins, consisting of 15−17 transmembrane helices per monomer, which hydrolyze pyrophosphate into orthophosphate.[11]

Summary

Corresponding Authors

Johansson − Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland; orcid.org/0000-0002-8226-4813. Ayman Khattab − Malaria Research Laboratory, Translational Immunology Research Program, Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, FI-00014 Helsinki, Finland. Seppo Meri − Malaria Research Laboratory, Translational Immunology Research Program, Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, FI-00014 Helsinki, Finland. Jari Yli-Kauhaluoma − Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland; orcid.org/0000-0003-0370-7653. Gustav Boije af Gennäs − Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland pubs.acs.org/acsmedchemlett. The manuscript was written through contributions of all authors. All authors have agreed to the final version of the manuscript

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