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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\u2019s food vacuoles, our approach is summarized as \u201cto dig its grave with its fork\u201d. 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.<\/jats:p>","DOI":"10.3390\/molecules29061397","type":"journal-article","created":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T04:34:46Z","timestamp":1710995686000},"page":"1397","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Hybrid Peptide-Alkoxyamine Drugs: A Strategy for the Development of a New Family of Antiplasmodial Drugs"],"prefix":"10.3390","volume":"29","author":[{"given":"Ange W.","family":"Embo-Ibouanga","sequence":"first","affiliation":[{"name":"Aix-Marseille University, CNRS, UMR 7273, 13007 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Nguyen","sequence":"additional","affiliation":[{"name":"LCC-CNRS, Laboratoire de Chimie de Coordination and MAAP, New Antimalarial Molecules and Pharmacological Approaches, 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\/0000-0003-0359-3959","authenticated-orcid":false,"given":"Lucie","family":"Paloque","sequence":"additional","affiliation":[{"name":"LCC-CNRS, Laboratoire de Chimie de Coordination and MAAP, New Antimalarial Molecules and Pharmacological Approaches, 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, 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France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rapha\u00ebl","family":"Bikanga","sequence":"additional","affiliation":[{"name":"Universit\u00e9 des Sciences et Techniques de Masuku, LASNSOM, BP 901 Franceville, Gabon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomie","family":"Coquin","sequence":"additional","affiliation":[{"name":"LCC-CNRS, Laboratoire de Chimie de Coordination and MAAP, New Antimalarial Molecules and Pharmacological Approaches, Inserm ERL 1289, Universit\u00e9 de Toulouse, CNRS, 31077 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9092-6776","authenticated-orcid":false,"given":"Anne","family":"Robert","sequence":"additional","affiliation":[{"name":"LCC-CNRS, Laboratoire de Chimie de Coordination and MAAP, New Antimalarial Molecules and Pharmacological Approaches, Inserm ERL 1289, Universit\u00e9 de Toulouse, CNRS, 31077 Toulouse, 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