Abstract
Conjugation of TP10, a cell-penetrating peptide with intrinsic antimalarial activity, to the well-known antimalarial drugs chloroquine and primaquine has been previously shown to enhance the peptide’s action against, respectively, blood- and liver-stage malaria parasites. Yet, this was achieved at the cost of a significant increase in haemolytic activity, as fluorescence microscopy and flow cytometry studies showed the conjugates to be more haemolytic for non-infected than for Plasmodium-infected red blood cells. To gain further insight into how these conjugates distinctively bind, and likely disrupt, membranes of both Plasmodium-infected and non-infected erythrocytes, we used dynamic light scattering and surface plasmon resonance to study the interactions of two representative conjugates and their parent compounds with lipid model membranes. Results obtained are herein reported and confirm that a strong membrane-disruptive character underlies the haemolytic properties of these conjugates, thus hampering their ability to exert selective antimalarial action.
Highlights
Malaria is unquestionably the most devastating parasitic disease worldwide, with a severe impact on at both health and economic levels; in 2018 alone, over 400,000 people died from this disease—mainly young children—and almost 230 million cases of malaria were reported [1]
The antimalarial drugs (AM)-TP10 conjugates were found to be substantially more haemolytic than their parent building blocks, and haemolysis by CQ-TP10 was observed to be more extensive on non-infected RBC (niRBC) than on PiRBC [18]. It appears that, upon coupling to AM, the original cell-penetrating ability of TP10 is converted into a cell-disruptive character that is more pronouncedly exerted onto niRBC than onto PiRBC. In view of these puzzling observations and considering the aforementioned differences between the membranes of unparasitized and parasitized RBC, we have investigated the interactions between two representative AM-TP10 conjugates (3 and 4, Figure 1) and large unilamellar vesicle (LUV)
Biophysical interactions between test compounds and zwitterionic/anionic lipid model membranes were investigated by surface plasmon and zwitterionic/anionic lipid model membranes were investigated by surface plasmon resonance (SPR) and dynamic light scattering (DLS), as follows
Summary
Malaria is unquestionably the most devastating parasitic disease worldwide, with a severe impact on at both health and economic levels; in 2018 alone, over 400,000 people died from this disease—mainly young children—and almost 230 million cases of malaria were reported [1]. While great progress has been made in reducing the burden of malaria, namely through the wide use of insecticide-treated mosquito nets for malaria prevention and the use of artemisinin-based combination therapy for treatment of infections, growing resistance to past and present antimalarial drugs (AM) still requires continued research to stay one step ahead [2] This is a difficult challenge, considering the complexity of the malaria parasite, whose lifecycle in the human host comprises different developmental exo- and intra-erythrocytic stages, each of which involves significant changes to the host cells upon parasite invasion. While cholesterol is distributed between the two halves or leaflets of the lipid bilayer, the other lipids are asymmetrically distributed: glycolipids, phosphatidylcholine (PC), and sphingomyelin (SM) are located in the outer leaflet; whereas phosphatidylinositol (PI), phosphatidylethanolamine (PE), and phosphatidylserine (PS)
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