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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\u2019s digestive enzymes to afford a highly labile alkoxyamine which homolyzes spontaneously and instantaneously into radicals\u2014which 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 \u00b5g\/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.<\/jats:p>","DOI":"10.3390\/pathogens13060482","type":"journal-article","created":{"date-parts":[[2024,6,6]],"date-time":"2024-06-06T08:45:37Z","timestamp":1717663537000},"page":"482","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Peptide-Alkoxyamine Drugs: An Innovative Approach to Fight Schistosomiasis: \u201cDigging Their Graves with Their Forks\u201d"],"prefix":"10.3390","volume":"13","author":[{"given":"Ange W.","family":"Embo-Ibouanga","sequence":"first","affiliation":[{"name":"Aix-Marseille University, CNRS, UMR 7273, Case 551, Avenue Escadrille Normandie-Niemen, CEDEX 20, 13397 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6496-0495","authenticated-orcid":false,"given":"Michel","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Laboratoire de Chimie de Coordination (LCC-CNRS) and, New Antimalarial Molecules and Pharmacological Approaches (MAAP), Inserm ERL 1289, Universit\u00e9 de Toulouse, CNRS, 31077 Toulouse, France"},{"name":"Institut de Pharmacologie et de Biologie Structurale (IPBS), Universit\u00e9 de Toulouse, CNRS, Universit\u00e9 Toulouse III\u2014Paul Sabatier (UPS), 31077 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4844-7499","authenticated-orcid":false,"given":"Jean-Patrick","family":"Joly","sequence":"additional","affiliation":[{"name":"Aix-Marseille University, CNRS, UMR 7273, Case 551, Avenue Escadrille Normandie-Niemen, CEDEX 20, 13397 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathilde","family":"Coustets","sequence":"additional","affiliation":[{"name":"Laboratoire de Chimie de Coordination (LCC-CNRS) and, New Antimalarial Molecules and Pharmacological Approaches (MAAP), Inserm ERL 1289, Universit\u00e9 de Toulouse, CNRS, 31077 Toulouse, France"},{"name":"Institut de Pharmacologie et de Biologie Structurale (IPBS), Universit\u00e9 de Toulouse, CNRS, Universit\u00e9 Toulouse III\u2014Paul Sabatier (UPS), 31077 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2847-1969","authenticated-orcid":false,"given":"Jean-Michel","family":"Augereau","sequence":"additional","affiliation":[{"name":"Laboratoire de Chimie de Coordination (LCC-CNRS) and, New Antimalarial Molecules and Pharmacological Approaches (MAAP), Inserm ERL 1289, Universit\u00e9 de Toulouse, CNRS, 31077 Toulouse, France"},{"name":"Institut de Pharmacologie et de 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Centrale Marseille ISM2, Case 531, Avenue Escadrille Normandie-Niemen, CEDEX 20, 13397 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rapha\u00ebl","family":"Bikanga","sequence":"additional","affiliation":[{"name":"Universit\u00e9 des Sciences et Techniques de Masuku, LASNSOM, Franceville BP 901, Gabon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9092-6776","authenticated-orcid":false,"given":"Anne","family":"Robert","sequence":"additional","affiliation":[{"name":"Laboratoire de Chimie de Coordination (LCC-CNRS) and, New Antimalarial Molecules and Pharmacological Approaches (MAAP), Inserm ERL 1289, Universit\u00e9 de Toulouse, CNRS, 31077 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9468-4823","authenticated-orcid":false,"given":"Fran\u00e7oise","family":"Benoit-Vical","sequence":"additional","affiliation":[{"name":"Laboratoire de 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