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

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

doi:10.1021/acsmedchemlett.9b00537

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

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

Research output: Contribution to journal › Article › Scientific › peer-review

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 mu M IC50 values in the Thermotoga maritima test system. Promisingly, the compounds retained activity against Plasmodium falciparum mPPase in membranes and inhibited parasite growth.

Original language	English
Journal	ACS Medicinal Chemistry Letters
Volume	11
Issue number	4
Pages (from-to)	605-610
Number of pages	6
ISSN	1948-5875
DOIs	https://doi.org/10.1021/acsmedchemlett.9b00537
Publication status	Published - 9 Apr 2020
MoE publication type	A1 Journal article-refereed

Fields of Science

ACIDOCALCISOMES
BISPHOSPHONATES
Membrane-bound pyrophosphatase
PUMPING PYROPHOSPHATASES
TARGET
TRYPANOSOMA-BRUCEI
drug design
isoxazoles
protozoan diseases
317 Pharmacy

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10.1021/acsmedchemlett.9b00537Licence: CC BY

acsmedchemlett.9b00537Final published version, 1.63 MBLicence: CC BY

Viikki Metabolomics Unit (LS-RIA/ Metabo-HiLIFE)
Sipari, N. (Manager)
Faculty of Biological and Environmental Sciences
Facility/equipment: Core Facility

Cite this

Johansson, N. G., Turku, A., Vidilaseris, K., Dreano, L., Khattab, A., Ayuso Perez, 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. (2020). Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment. ACS Medicinal Chemistry Letters, 11(4), 605-610. https://doi.org/10.1021/acsmedchemlett.9b00537

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title = "Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment",

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 mu M IC50 values in the Thermotoga maritima test system. Promisingly, the compounds retained activity against Plasmodium falciparum mPPase in membranes and inhibited parasite growth.",

keywords = "ACIDOCALCISOMES, BISPHOSPHONATES, Membrane-bound pyrophosphatase, PUMPING PYROPHOSPHATASES, TARGET, TRYPANOSOMA-BRUCEI, drug design, isoxazoles, protozoan diseases, 317 Pharmacy",

author = "Johansson, {Niklas G} and Ainoleena Turku and Keni Vidilaseris and Loic Dreano and Ayman Khattab and {Ayuso Perez}, Daniel and Aaron Wilkinson and Yuezhou Zhang and Matti Tamminen and Evgeni Grazhdankin and Alexandros Kiriazis and Fishwick, {Colin W. G.} and Seppo Meri and Jari Yli-Kauhaluoma and Adrian Goldman and {Boije af Genn{\"a}s}, Gustav and Henri Xhaard",

year = "2020",

month = apr,

day = "9",

doi = "10.1021/acsmedchemlett.9b00537",

language = "English",

volume = "11",

pages = "605--610",

journal = "ACS Medicinal Chemistry Letters",

issn = "1948-5875",

publisher = "American Chemical Society",

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Johansson, NG , Turku, A , Vidilaseris, K , Dreano, L , Khattab, A, Ayuso Perez, D, Wilkinson, A, Zhang, Y, Tamminen, M, Grazhdankin, E, Kiriazis, A, Fishwick, CWG, Meri, S , Yli-Kauhaluoma, J , Goldman, A, Boije af Gennäs, G & Xhaard, H 2020, 'Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment', ACS Medicinal Chemistry Letters, vol. 11, no. 4, pp. 605-610. https://doi.org/10.1021/acsmedchemlett.9b00537

TY - JOUR

T1 - Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment

AU - Johansson, Niklas G

AU - Turku, Ainoleena

AU - Vidilaseris, Keni

AU - Dreano, Loic

AU - Khattab, Ayman

AU - Ayuso Perez, Daniel

AU - Wilkinson, Aaron

AU - Zhang, Yuezhou

AU - Tamminen, Matti

AU - Grazhdankin, Evgeni

AU - Kiriazis, Alexandros

AU - Fishwick, Colin W. G.

AU - Meri, Seppo

AU - Yli-Kauhaluoma, Jari

AU - Goldman, Adrian

AU - Boije af Gennäs, Gustav

AU - Xhaard, Henri

PY - 2020/4/9

Y1 - 2020/4/9

N2 - 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 mu M IC50 values in the Thermotoga maritima test system. Promisingly, the compounds retained activity against Plasmodium falciparum mPPase in membranes and inhibited parasite growth.

AB - 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 mu M IC50 values in the Thermotoga maritima test system. Promisingly, the compounds retained activity against Plasmodium falciparum mPPase in membranes and inhibited parasite growth.

KW - ACIDOCALCISOMES

KW - BISPHOSPHONATES

KW - Membrane-bound pyrophosphatase

KW - PUMPING PYROPHOSPHATASES

KW - TARGET

KW - TRYPANOSOMA-BRUCEI

KW - drug design

KW - isoxazoles

KW - protozoan diseases

KW - 317 Pharmacy

U2 - 10.1021/acsmedchemlett.9b00537

DO - 10.1021/acsmedchemlett.9b00537

M3 - Article

SN - 1948-5875

VL - 11

SP - 605

EP - 610

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 4

ER -

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

Abstract

Fields of Science

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Equipment

Viikki Metabolomics Unit (LS-RIA/ Metabo-HiLIFE)

Cite this