Abstract
SummaryThe attachment of myristate to the N-terminal glycine of certain proteins is largely a co-translational modification catalyzed by N-myristoyltransferase (NMT), and involved in protein membrane-localization. Pathogen NMT is a validated therapeutic target in numerous infectious diseases including malaria. In Plasmodium falciparum, NMT substrates are important in essential processes including parasite gliding motility and host cell invasion. Here, we generated parasites resistant to a particular NMT inhibitor series and show that resistance in an in vitro parasite growth assay is mediated by a single amino acid substitution in the NMT substrate-binding pocket. The basis of resistance was validated and analyzed with a structure-guided approach using crystallography, in combination with enzyme activity, stability, and surface plasmon resonance assays, allowing identification of another inhibitor series unaffected by this substitution. We suggest that resistance studies incorporated early in the drug development process help selection of drug combinations to impede rapid evolution of parasite resistance.
Highlights
Malaria, caused by parasitic protozoa of the genus Plasmodium, led to an estimated 216 million clinical cases and nearly half a million deaths in 2016 (World Health Organization, 2017)
The attachment of myristate to the N-terminal glycine of certain proteins is largely a co-translational modification catalyzed by N-myristoyltransferase (NMT), and involved in protein membrane-localization
IMP-1002 is a previously undisclosed member of our recently reported series of human NMT inhibitors (Mousnier et al, 2018), and a close analog of IMP0917 (Figure S1) that was discovered through a fragment reconstruction approach based on hits from screens against P. vivax NMT (PvNMT) and PfNMT
Summary
Malaria, caused by parasitic protozoa of the genus Plasmodium, led to an estimated 216 million clinical cases and nearly half a million deaths in 2016 (World Health Organization, 2017). The enzyme NMT, which acylates the N-terminal glycine of substrate proteins, is a promising target for antimalarial drug development (Wright et al, 2014) This enzyme is important for the survival and viability of a wide range of parasites (Plasmodium, Leishmania, and Trypanosoma species) and fungi (Bell et al, 2012; Brannigan et al, 2010; Fang et al, 2015; Frearson et al, 2010; Goncalves et al, 2012b; Hutton et al, 2014; Mousnier et al, 2018; Olaleye et al, 2014; Rackham et al, 2014; Schlott et al, 2018; Tate et al, 2013; Wright et al, 2014, 2016; 2015; Yu et al, 2012), which each encode a single nmt gene (PF3D7_1412800). The design of inhibitors against both P. falciparum (Pf) and P. vivax (Pv) NMTs has
Sign-in/Register to view highlights & summary 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.
