Aquaporin Inhibition by Gold(III) Compounds: New Insights

Abstract

Aquaporins (AQPs) are membrane water/glycerol channels with essential roles in biological systems, as well as being promising targets for therapy and imaging. Using a stopped-flow method, a series of gold(III), platinum(II) and copper(II) complexes bearing nitrogen donor ligands, such as 1,10-phenatroline, 2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 4,4'-diamino-2,2'-bipyridine and 2,2';6',2"-terpyridine, were evaluated in human red blood cells expressing AQP1 and AQP3, responsible for water and glycerol movement, respectively. The results showed that the gold(III) complexes selectively modulate AQP3 over AQP1. Molecular modeling and density functional theory (DFT) calculations were subsequently performed to rationalize the observations and to investigate the possible molecular mechanism through which these gold compounds act on their putative target (AQP3). In the absence of any crystallographic data, a previously reported homology model was used for this purpose. Combined, the findings of this study show that potent and selective modulation of these solute channels is possible, however further investigation is required into the selectivity of this class of agents against all AQP isoforms and their potential therapeutic uses.

Nanoformulations of a Potent copper-based Aquaporin Inhibitor With Cytotoxic Effect Against Cancer Cells

“…The same strategy can be easily adapted for other metallodrugs such as the gold(III) complex Auphen that shows even higher AQP3 inhibition ability [14] . Further studies are certainly necessary to validate inhibition of AQP3 as the main target responsible for the anticancer effects of Cuphen and similar metal compounds, as well as to assess Cuphen anticancer activity in vivo.…”

“…Dose-response curves are shown in Figure 2 and the IC 50 values obtained from data fits are summarized in Table 1. Inhibition of glycerol permeability in hRBC by the same metal complexes [13,14] is also reported for comparison purposes. As shown in Figure 2, the cellular behavior under the influence of the phenanthroline compounds (Auphen and Cuphen) differs significantly from the bipyridine cores (p <0.001).…”

“…Moreover, the majority fails to undergo to clinical trials due to extreme toxicity. Recently, Martins et al described new gold-based coordination compounds as potent and selective inhibitors of the glycerol transport through AQP3 in human red blood cells (hRBC) [13,14]. Interestingly, all these gold complexes contain N-donor ligands and are also described as antiproliferative agents against cancer cells in vitro [15 -17] .…”

Aquaporins: important but elusive drug targets

“…AQP binding and the selectivity of the AQP3-targeting gold (III) inhibitors was investigated using homology modelling and docking, with inhibitor binding characterized by density functional theory calculations. It was hypothesized that the inhibitors interact with the accessible Cys40 residue on the extracellular side of AQP3, with the traditional metal-binding residue Cys189 in AQP1 not favourably positioned to interact with these compounds 126,127 .…”

“…This may be especially true for AQPs because of their small molecular size and narrow aqueous pore. This issue is highlighted by the gold-containing inhibitor Au(phen), which blocks glycerol transport by AQP3 but not water transport 126,127 , perhaps owing to insufficient channel occlusion. More sophisticated molecular dynamics-based approaches have been explored to model AQP inhibition, which involve the calculation of water permeability coefficients 145 ; however, these approaches were computationally intensive and water permeability coefficients did not correlate with inhibitory efficacy.…”