Evaluation of gold-based compounds as Plasmodium falciparum aquaglyceroporin inhibitors

Abstract

The efficiency of gold complexes featuring di- or tri-pyridine scaffolds in inhibiting human aquaporins have been previously investigated. They have returned promising results in cancer treatment and have been suggested to be potentially applied against malaria too. ([Au(bipy) Cl_2]+)., ([Au(phen)Cl_2]+) and ([Au(terpy)Cl]2+) in all their possible forms in solution, were computationally studied using Molecular Dynamics (MD) to investigate whether they could inhibit the permeation of glycerol and/or water in the malaria parasite Plasmodium falciparum through its single aquaglyceroprotein. The target was chosen due to its similarity with other aquaporins that are known to be inhibited by these complexes, and showed conserved interactions with residues lining the pore. In particular, the model suggested how both the chloride and the hydroxide complexes of [Au(terpy)Cl]2+ ,together with [([Au(phen)Cl_2]+ ,yield the most efficient inhibition of the channel. These predictions were proven via in vitro assays, thus demonstrating the validity of the computational method. [Au(terpy)Cl]2+ gave the most efficient reduction in parasitemia, with and IC50 of 0.37 μM (FCR3, chloroquine resistant strain), and [([Au(phen)Cl_2]+ had to be administered in higher concentration to return the desired effect (IC50 of 2.60 μM FCR3 resistant strain).
Therefore, the compounds were proven to be active even in the absence of combination with chloroquine. These results are thus promising for the development of a novel approach to treat malaria.

Popular Abstract

Malaria accounts for hundreds of thousand of deaths every year, mostly in the poorest regions of the globe and especially in sub-Saharan Africa. The difficult socio-economic conditions of the area contribute to the complications of stemming the parasite diffusion and overcoming resistance to known drugs and therefore, to treatment issues. Such a situation requires to be tackled from multiple points of view, from improving general sanitary conditions to developing new compounds and/or finding new exploitable targets. Currently, five strains of the parasite responsible for this disease in humans are known and they show different infectiousness and mortality. They also respond differently to treatments, but the current medicines are efficient against them all, albeit to different extents. This study focuses on the deadliest strain, accounting for nearly 80 % of the deaths, namely Plasmodium falciparum. Parasites such as this one are treated by the administration of a combination of several drugs, that aim to slow down proliferation or kill the undesired pathogen, and therefore have different targets.
In the present study, some gold complexes, previously known to the medical community, have been investigated, focusing on the possibility to inhibit a membrane protein that is fundamental to the parasite life-cycle. Such gold-based complexes have already been noticed to inhibit some human transmembrane channel proteins belonging to the class of aquaglyceroproteins, which are responsible for osmotic balance and glycerol uptake functions that are necessary for the synthesis of cell membranes during multiplication phases. Such proteins have received particular interest due to the fact that they appear to be over-expressed over cancer cell membranes, as this kind of cells requires more nutrients because of their high growth rate. The inhibition of these protein channels has been linked to malaria treatment as it seems to be potentially effective in slowing down the parasite proliferation because the parasite exploits our very own membrane proteins for its personal glycerol intake. Despite that, our bodies require human aquaporins to be functioning for their own sake; therefore inhibition of these aquaporins would perhaps slow down the parasite proliferation, but it would also return some more or less serious side-effects.
The novelty of this study consists in targeting not the human aquaporins, but the single parasite aquaglyceroprotein. This way, our cells could continue taking up glycerol for their correct functioning, while selectively depriving the parasite cells. Nevertheless, for the compounds to be fully selective towards PfAQP (Plasmodium falciparum aquaglyceroporin), additional modifications might need to be exploited. On the other hand, targeting the parasite protein to find out whether it can be inhibited by these complexes in the first place is the first step in this direction.
Starting from a computational approach, the drug candidates under investigation are expected to block the entrance of glycerol through the pore and, therefore, be considered worth to be tested on the parasite in vitro. The tests on live parasite showed that the results are in line with the observed activities: Auterpy ([Au(terpy)Cl]2+) gave the best inhibition efficiency, followed by Auphen ([Au(phen)Cl_2]+) and Aubipy ([Au(bipy) Cl_2]+). Therefore, all tested compounds are promising building blocks for targeting PfAQP, alone or in combination with known antimalarials, such as chloroquine.

• author: Balgera, Federico
• supervisor: Ricardo Ferreira
• organization: Department of Chemistry
• course: KEMR10 20221
• year: 2022
• type: H2 - Master's Degree (Two Years)
• subject: Chemistry
• keywords: Malaria, Plasmodium falciparum, gold complexes, biochemistry
• language: English
• id: 9102461
• date added to LUP: 2022-11-04 10:48:37
• date last changed: 2022-11-04 10:48:37