Abstract
Current malaria treatments are threatened by drug resistance and new drugs are urgently needed. In a phenotypic screen for new antimalarials, we identified (S)-SW228703 ((S)-SW703), a tyrosine amide with asexual blood and liver stage activity and a fast-killing profile. Resistance to (S)-SW703 is associated with mutations in Plasmodium falciparum cyclic amine resistance locus (PfCARL) and P. falciparum acetyl CoA transporter (PfACT), similarly to several other compounds that share features such as fast activity and liver-stage activity. Compounds with these resistance mechanisms are thought to act in the ER, though their target(s) are unknown. The tyramine of (S)-SW703 is shared with some reported PfCARL-associated compounds; however, we observed that strict S-stereochemistry was required for activity of (S)-SW703, suggesting differences in mechanism of action or binding mode. (S)-SW703 provides a new chemical series with broad activity on multiple life-cycle stages and a fast-killing mechanism of action, available for lead optimization to generate new treatments for malaria.
Competing Interest Statement
BL is a Medicines for Malaria Venture (MMV) employee. Otherwise, the authors declare no competing financial interest.
Abbreviations used
- ATQ
- atovaquone
- BRRoK
- bioluminescence relative rate of kill
- CLint
- intrinsic clearance
- CQ
- chloroquine
- CYC
- cycloguanil
- Dd2-Polδ
- Dd2 with mutant DNA polymerase δ
- DGFA
- dual gamete formation assay
- DMSO
- dimethylsulfoxide
- eIF2α
- eukaryotic translation initiation factor 2 alpha subunit
- ER
- endoplasmic reticulum
- FACS
- fluorescence-activated single cell sorting
- IGF
- insulin-like growth factor
- MDR1
- multidrug resistance protein 1
- MMV048
- MMV390048
- PfACT
- P. falciparum acetyl-coA transporter
- PfCARL
- P. falciparum cyclic amine resistance locus
- PfUGT
- P. falciparum UDP-galactose transporter
- PI4K
- phosphatidylinositol 4-kinase
- PPQ
- piperaquine
- PYR
- pyrimethamine
- RBCs
- red blood cells
- SD
- standard deviation
- (S)-SW703
- (S)-SW228703
- WT
- wildtype.