Bilayer Effects of Antimalarial Compounds.

Nicole B Ramsey,Olaf S Andersen

doi:10.1371/journal.pone.0142401

Nicole B Ramsey, Olaf S Andersen

Open Access

https://doi.org/10.1371/journal.pone.0142401

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Abstract

Because of the perpetual development of resistance to current therapies for malaria, the Medicines for Malaria Venture developed the Malaria Box to facilitate the drug development process. We tested the 80 most potent compounds from the box for bilayer-mediated effects on membrane protein conformational changes (a measure of likely toxicity) in a gramicidin-based stopped flow fluorescence assay. Among the Malaria Box compounds tested, four compounds altered membrane properties (p< 0.05); MMV007384 stood out as a potent bilayer-perturbing compound that is toxic in many cell-based assays, suggesting that testing for membrane perturbation could help identify toxic compounds. In any case, MMV007384 should be approached with caution, if at all.

Highlights

Data Availability Statement: All relevant data are within the paper and its Supporting Information files
Using quench rates determined from the fluorescence traces, dose-response curves (1–10 μM) were constructed for each compound; the results are summarized in S1 Fig. To visualize whether the Malaria Box compounds alter lipid bilayer properties, Fig 2 shows the normalized rates for each compound at 5 μM
We explored whether the compounds provided in the Malaria Box have significant bilayer-modifying effects

Summary

Introduction

Data Availability Statement: All relevant data are within the paper and its Supporting Information files. It long has been appreciated that drugs may alter lipid bilayer properties [13], and druginduced in lipid bilayer structure and dynamics have been demonstrated using a variety of spectroscopic methods in the case of antidepressants [14, 15] phytochemicals [16, 17] and antimicrobial peptides [18, 19]—and many biologically active amphiphiles alter lipid bilayer properties and integral membrane protein function at similar concentrations [20,21,22,23,24,25] This bilayer regulation of membrane protein function arises because membrane protein function depends on conformational transitions that involve the proteins’ bilayer-spanning domains–leading to alterations in lipid packing adjacent to the proteins of interest. Would the Malaria Box compounds have a similar proportion of compounds that modulate bilayer properties?

Materials and Methods

Results

Discussion