A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission
To combat drug resistance, new chemical entities are urgently required for use in next generation anti-malarial combinations. We report here the results of a medicinal chemistry programme focused on an imidazopyridine series targeting the Plasmodium falciparum cyclic GMP-dependent protein kinase (Pf...
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Veröffentlicht in: | Nature communications 2017-09, Vol.8 (1), p.430-9, Article 430 |
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Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | To combat drug resistance, new chemical entities are urgently required for use in next generation anti-malarial combinations. We report here the results of a medicinal chemistry programme focused on an imidazopyridine series targeting the
Plasmodium falciparum
cyclic GMP-dependent protein kinase (PfPKG). The most potent compound (ML10) has an IC
50
of 160 pM in a PfPKG kinase assay and inhibits
P. falciparum
blood stage proliferation in vitro with an EC
50
of 2.1 nM. Oral dosing renders blood stage parasitaemia undetectable in vivo using a
P. falciparum
SCID mouse model. The series targets both merozoite egress and erythrocyte invasion, but crucially, also blocks transmission of mature
P. falciparum
gametocytes to
Anopheles stephensi
mosquitoes. A co-crystal structure of PvPKG bound to ML10, reveals intimate molecular contacts that explain the high levels of potency and selectivity we have measured. The properties of this series warrant consideration for further development to produce an antimalarial drug.
Protein kinases are promising drug targets for treatment of malaria. Here, starting with a medicinal chemistry approach, Baker et al. generate an imidazopyridine that selectively targets
Plasmodium falciparum
PKG, inhibits blood stage parasite growth in vitro and in mice and blocks transmission to mosquitoes. |
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ISSN: | 2041-1723 2041-1723 |
DOI: | 10.1038/s41467-017-00572-x |