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

[Image: see text] 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 frag...

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Autores principales: Johansson, Niklas G., Turku, Ainoleena, Vidilaseris, Keni, Dreano, Loïc, Khattab, Ayman, Ayuso Pérez, Daniel, Wilkinson, Aaron, Zhang, Yuezhou, Tamminen, Matti, Grazhdankin, Evgeni, Kiriazis, Alexandros, Fishwick, Colin W. G., Meri, Seppo, Yli-Kauhaluoma, Jari, Goldman, Adrian, Boije af Gennäs, Gustav, Xhaard, Henri
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153278/
https://www.ncbi.nlm.nih.gov/pubmed/32292570
http://dx.doi.org/10.1021/acsmedchemlett.9b00537
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author Johansson, Niklas G.
Turku, Ainoleena
Vidilaseris, Keni
Dreano, Loïc
Khattab, Ayman
Ayuso Pérez, Daniel
Wilkinson, Aaron
Zhang, Yuezhou
Tamminen, Matti
Grazhdankin, Evgeni
Kiriazis, Alexandros
Fishwick, Colin W. G.
Meri, Seppo
Yli-Kauhaluoma, Jari
Goldman, Adrian
Boije af Gennäs, Gustav
Xhaard, Henri
author_facet Johansson, Niklas G.
Turku, Ainoleena
Vidilaseris, Keni
Dreano, Loïc
Khattab, Ayman
Ayuso Pérez, Daniel
Wilkinson, Aaron
Zhang, Yuezhou
Tamminen, Matti
Grazhdankin, Evgeni
Kiriazis, Alexandros
Fishwick, Colin W. G.
Meri, Seppo
Yli-Kauhaluoma, Jari
Goldman, Adrian
Boije af Gennäs, Gustav
Xhaard, Henri
author_sort Johansson, Niklas G.
collection PubMed
description [Image: see text] 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 IC(50) values in the Thermotoga maritima test system. Promisingly, the compounds retained activity against Plasmodium falciparum mPPase in membranes and inhibited parasite growth.
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spelling pubmed-71532782020-04-14 Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment Johansson, Niklas G. Turku, Ainoleena Vidilaseris, Keni Dreano, Loïc Khattab, Ayman Ayuso Pérez, Daniel Wilkinson, Aaron Zhang, Yuezhou Tamminen, Matti Grazhdankin, Evgeni Kiriazis, Alexandros Fishwick, Colin W. G. Meri, Seppo Yli-Kauhaluoma, Jari Goldman, Adrian Boije af Gennäs, Gustav Xhaard, Henri ACS Med Chem Lett [Image: see text] 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 IC(50) values in the Thermotoga maritima test system. Promisingly, the compounds retained activity against Plasmodium falciparum mPPase in membranes and inhibited parasite growth. American Chemical Society 2020-02-17 /pmc/articles/PMC7153278/ /pubmed/32292570 http://dx.doi.org/10.1021/acsmedchemlett.9b00537 Text en Copyright © 2020 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle Johansson, Niklas G.
Turku, Ainoleena
Vidilaseris, Keni
Dreano, Loïc
Khattab, Ayman
Ayuso Pérez, Daniel
Wilkinson, Aaron
Zhang, Yuezhou
Tamminen, Matti
Grazhdankin, Evgeni
Kiriazis, Alexandros
Fishwick, Colin W. G.
Meri, Seppo
Yli-Kauhaluoma, Jari
Goldman, Adrian
Boije af Gennäs, Gustav
Xhaard, Henri
Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment
title Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment
title_full Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment
title_fullStr Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment
title_full_unstemmed Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment
title_short Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment
title_sort discovery of membrane-bound pyrophosphatase inhibitors derived from an isoxazole fragment
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153278/
https://www.ncbi.nlm.nih.gov/pubmed/32292570
http://dx.doi.org/10.1021/acsmedchemlett.9b00537
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