Abstract
Guttiferone A (GA) 1, a polycyclic polyprenylated acylphloroglucinol (PPAP) isolated from the plant Symphonia globulifera (Clusiaceae), constitutes a novel hit in antimalarial drug discovery. PPAPs do not possess identified biochemical targets in malarial parasites up to now. Towards this aim, we designed and evaluated a natural product-derived photoactivatable probe AZC-GA 5, embedding a photoalkylative fluorogenic motif of the 7-azidocoumarin (AZC) type, devoted to studying the affinity proteins interacting with GA in Plasmodium falciparum. Probe 5 manifested a number of positive functional and biological features, such as (i) inhibitory activity in vitro against P. falciparum blood-stages that was superimposable to that of GA 1, dose–response photoalkylative fluorogenic properties (ii) in model conditions using bovine serum albumin (BSA) as an affinity protein surrogate, (iii) in live P. falciparum-infected erythrocytes, and (iv) in fresh P. falciparum cell lysate. Fluorogenic signals by photoactivated AZC-GA 5 in biological settings were markedly abolished in the presence of excess GA 1 as a competitor, indicating significant pharmacological specificity of the designed molecular probe relative to the native PPAP. These results open the way to identify the detected plasmodial proteins as putative drug targets for the natural product 1 by means of proteomic analysis.
Highlights
Malaria, a devastating tropical disease caused by protozoan parasites of the genus Plasmodium, is currently responsible for ca. 400,000 deaths annually [1]
PPAPs correspond to unprecedented scaffolds in antiplasmodial pharmacochemistry, Guttiferone A (GA) 1 itself featuring a compact hexa-oxygenated core decorated with four prenyle chains
Regarding structure–activity relationships (SARs) in the series, a number of preliminary modifications performed on the catechol subunit of 1 previously showed that monoor bis-esterification of the catechol even by some relatively bulky moieties were maintaining the antiplasmodial activity of the natural PPAP (Figure 2) [11]
Summary
A devastating tropical disease caused by protozoan parasites of the genus Plasmodium, is currently responsible for ca. 400,000 deaths annually [1]. Artemisinin derivatives still constitute the frontline antimalarials prescribed worldwide, and are estimated to have saved millions of lives during the last two decades due to their fast curative action, against the most deadly and Africa-prevalent P. falciparum [2]. These progresses are threatened by the spread of artemisinin-resistant parasite strains, which emerged one decade ago in South-East Asia [3]. This phenomenon is a worrying continuum of the history of chemoresistance to most major antimalarials [4]. Antimalarial action is a common trend amongst various PPAPs (Figure 1) [13,14,15,16,17,18,19], suggesting that these natural products interact with promiscuous classes of targets within the parasite—possibly sirtuins [20,21,22] and mitochondrial proteins [19,23,24,25]—which, remained elusive up to now
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