Hybrid Peptide-Alkoxyamine Drugs: A Strategy for the Development of a New Family of Antiplasmodial Drugs

Abstract

The emergence and spread of drug-resistant Plasmodium falciparum parasites shed a serious concern on the worldwide control of malaria, the most important tropical disease in terms of mortality and morbidity. This situation has led us to consider the use of peptide-alkoxyamine derivatives as new antiplasmodial prodrugs that could potentially be efficient in the fight against resistant malaria parasites. Indeed, the peptide tag of the prodrug has been designed to be hydrolysed by parasite digestive proteases to afford highly labile alkoxyamines drugs, which spontaneously and instantaneously homolyse into two free radicals, one of which is expected to be active against P. falciparum. Since the parasite enzymes should trigger the production of the active drug in the parasite’s food vacuoles, our approach is summarized as “to dig its grave with its fork”. However, despite promising sub-micromolar IC50 values in the classical chemosensitivity assay, more in-depth tests evidenced that the anti-parasite activity of these compounds could be due to their cytostatic activity rather than a truly anti-parasitic profile, demonstrating that the antiplasmodial activity cannot be based only on measuring antiproliferative activity. It is therefore imperative to distinguish, with appropriate tests, a genuinely parasiticidal activity from a cytostatic activity.

Peptide-Alkoxyamine Drugs: An Innovative Approach to Fight Schistosomiasis: “Digging Their Graves with Their Forks”

“…Due to technical problems, it was not possible to perform cytotoxicity in the same concentrations as those used for toxicity experiments on schistosomes. Nevertheless, the cytotoxicity (CC 50 > 50 μM) obtained on VERO cells after 48 h of treatment and reported for Plasmodium [ 12 ] shows that these molecules are rather inactive in mammalian cells [ 26 ]. Then, the approach developed in Scheme 1 may have involved different parts of the alkoxyamines in the inhibition processes both for toxicity and cytotoxicity.…”

“…Interestingly, all models from the L series, whether peptides alone or hybrid compounds, are non-cytotoxic (cytotoxicity concentration CC 50 > 50 μM) [ 12 ]. Importantly, peptide-alkoxyamine hybrids in the natural series L are stable in our experimental conditions and not cytotoxic at 50 μM, confirming their specificity on schistosome.…”

“…Therefore, drawing on our experience with alkoxyamines’ efficiency against tumors [ 6 ] and Plasmodium [ 12 ], alkoxyamines A3L – A7L ( Figure 1 ) carrying the peptide sequence L-Phe-Val-Phe-OH are tested (More details are provided in [ 12 ]). For comparison, the series D made of unnatural peptides is also investigated ( Figure 1 ).…”

Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

“…Protein alkylation, more than just a target for antimalarials, is often the actual mechanism of action, or part of a more complex operation, for numerous antimalarials, including artemisinin, one of the primary antimalarial drugs [ 347 , 348 , 349 , 350 ]. Only a few examples of protein alkylation targeting are reported here.…”