Abstract
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 IC50 of 160 pM in a PfPKG kinase assay and inhibits P. falciparum blood stage proliferation in vitro with an EC50 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.
Highlights
To combat drug resistance, new chemical entities are urgently required for use in generation anti-malarial combinations
This has led to concerns about the emergence and spread of resistance to these relatively new medicines, which are the mainstay globally for the treatment of malaria caused by Plasmodium falciparum[6, 7]
All mammalian PKGs and most serine/threonine kinases have a large gatekeeper residue[11] preventing access to the pocket and making them insensitive to the PKG inhibitors mentioned above and likely explaining the high levels of selectivity observed[9, 10]. These PKG inhibitors block the development of a number of Plasmodium life cycle stages[12,13,14,15,16,17,18] and we have used a chemical genetic approach that exploits the small gatekeeper residue in PfPKG to generate an inhibitorresistant P. falciparum transgenic line (T618Q), to demonstrate that this enzyme plays an essential role in blood stage replication in the human host as well as gametogenesis and ookinete motility in the mosquito vector
Summary
New chemical entities are urgently required for use in generation anti-malarial combinations. All mammalian PKGs and most serine/threonine kinases have a large gatekeeper residue[11] preventing access to the pocket and making them insensitive to the PKG inhibitors mentioned above and likely explaining the high levels of selectivity observed[9, 10] These PKG inhibitors block the development of a number of Plasmodium life cycle stages[12,13,14,15,16,17,18] and we have used a chemical genetic approach that exploits the small gatekeeper residue in PfPKG to generate an inhibitorresistant P. falciparum transgenic line (T618Q), to demonstrate that this enzyme plays an essential role in blood stage replication in the human host as well as gametogenesis and ookinete motility in the mosquito vector. We present co-crystal structures of P. vivax PKG with the inhibitors, which reveal the interactions underpinning the high degree of selectivity we have observed
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
