Peptide-Alkoxyamine Drugs: An Innovative Approach to Fight Schistosomiasis: “Digging Their Graves with Their Forks”
Ange W. Embo-Ibouanga,
Michel Nguyen,
Jean-Patrick Joly,
Mathilde Coustets,
Jean-Michel Augereau,
Lucie Paloque,
Nicolas Vanthuyne,
Raphaël Bikanga,
Anne Robert,
Françoise Benoit-Vical,
Gérard Audran,
Philippe Mellet,
Jérôme Boissier,
Sylvain R. A. Marque
Affiliations
Ange W. Embo-Ibouanga
Aix-Marseille University, CNRS, UMR 7273, Case 551, Avenue Escadrille Normandie-Niemen, CEDEX 20, 13397 Marseille, France
Michel Nguyen
Laboratoire de Chimie de Coordination (LCC-CNRS) and, New Antimalarial Molecules and Pharmacological Approaches (MAAP), Inserm ERL 1289, Université de Toulouse, CNRS, 31077 Toulouse, France
Jean-Patrick Joly
Aix-Marseille University, CNRS, UMR 7273, Case 551, Avenue Escadrille Normandie-Niemen, CEDEX 20, 13397 Marseille, France
Mathilde Coustets
Laboratoire de Chimie de Coordination (LCC-CNRS) and, New Antimalarial Molecules and Pharmacological Approaches (MAAP), Inserm ERL 1289, Université de Toulouse, CNRS, 31077 Toulouse, France
Jean-Michel Augereau
Laboratoire de Chimie de Coordination (LCC-CNRS) and, New Antimalarial Molecules and Pharmacological Approaches (MAAP), Inserm ERL 1289, Université de Toulouse, CNRS, 31077 Toulouse, France
Lucie Paloque
Laboratoire de Chimie de Coordination (LCC-CNRS) and, New Antimalarial Molecules and Pharmacological Approaches (MAAP), Inserm ERL 1289, Université de Toulouse, CNRS, 31077 Toulouse, France
Nicolas Vanthuyne
Aix-Marseille University, CNRS, Centrale Marseille ISM2, Case 531, Avenue Escadrille Normandie-Niemen, CEDEX 20, 13397 Marseille, France
Raphaël Bikanga
Université des Sciences et Techniques de Masuku, LASNSOM, Franceville BP 901, Gabon
Anne Robert
Laboratoire de Chimie de Coordination (LCC-CNRS) and, New Antimalarial Molecules and Pharmacological Approaches (MAAP), Inserm ERL 1289, Université de Toulouse, CNRS, 31077 Toulouse, France
Françoise Benoit-Vical
Laboratoire de Chimie de Coordination (LCC-CNRS) and, New Antimalarial Molecules and Pharmacological Approaches (MAAP), Inserm ERL 1289, Université de Toulouse, CNRS, 31077 Toulouse, France
Gérard Audran
Aix-Marseille University, CNRS, UMR 7273, Case 551, Avenue Escadrille Normandie-Niemen, CEDEX 20, 13397 Marseille, France
Philippe Mellet
Magnetic Resonance of Biological Systems, UMR 5536 CNRS-University of Bordeaux, 146 rue Leo Saignat, CEDEX, 33076 Bordeaux, France
Jérôme Boissier
IHPE, CNRS, Ifremer, University Perpignan Via Domitia, 66860 Perpignan, France
Sylvain R. A. Marque
Aix-Marseille University, CNRS, UMR 7273, Case 551, Avenue Escadrille Normandie-Niemen, CEDEX 20, 13397 Marseille, France
The expansion of drug resistant parasites sheds a serious concern on several neglected parasitic diseases. Our recent results on cancer led us to envision the use of peptide-alkoxyamines as a highly selective and efficient new drug against schistosome adult worms, the etiological agents of schistosomiasis. Indeed, the peptide tag of the hybrid compounds can be hydrolyzed by worm’s digestive enzymes to afford a highly labile alkoxyamine which homolyzes spontaneously and instantaneously into radicals—which are then used as a drug against Schistosome adult parasites. This approach is nicely summarized as digging their graves with their forks. Several hybrid peptide-alkoxyamines were prepared and clearly showed an activity: two of the tested compounds kill 50% of the parasites in two hours at a concentration of 100 µg/mL. Importantly, the peptide and alkoxyamine fragments that are unable to generate alkyl radicals display no activity. This strong evidence validates the proposed mechanism: a specific activation of the prodrugs by the parasite proteases leading to parasite death through in situ alkyl radical generation.
