Sébastien Pomel1, Sandrine Cojean1, Valérie Pons2, Jean-Christophe Cintrat2, Laetitia Nguyen3, Joël Vacus4, Alain Pruvost3, Julien Barbier5, Daniel Gillet5, Philippe M Loiseau1. 1. Université Paris-Saclay, CNRS, BioCIS, 92290, Châtenay-Malabry, France. 2. Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SCBM, 91191, Gif-sur-Yvette, France. 3. Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SPI, 91191, Gif-sur-Yvette, France. 4. Drugabilis, 7, Allée de Londres, 91140, Villejust, France. 5. Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SIMoS, 91191, Gif-sur-Yvette, France.
Abstract
BACKGROUND: This study aimed to investigate compounds acting on the host cell machinery to impair parasite installation with the possible advantage of limiting drug resistance. The strategy therefore consisted of selecting compounds that are poorly active on the axenic parasite, but very active on the intramacrophage form of Leishmania. OBJECTIVES: To identify a drug candidate from focused screening of adamantamine derivatives that can inhibit the development of Leishmania infantum in macrophages. METHODS: In vitro screening was performed on a library of 142 adamantamine derivatives with axenic and intramacrophage forms of L. infantum, as well as cytotoxicity assays, allowing selection of the most promising compound. Absorption, distribution, metabolism and excretion (ADME) experiments, including pharmacokinetics and microsomal stability, were performed and finally the physicochemical stability of the compound was investigated to assess its suitability for further drug development. RESULTS: VP343 was identified first in vitro, with a CC50 value of 63.7 μM and an IC50 value of 0.32 μM for L. infantum intramacrophage amastigotes and then in vivo, with a 59% reduction of the liver parasite burden after oral administration at 10 mg/kg/day for 5 days. In addition, the ADME data were compatible with moving this compound further through the antileishmanial drug candidate pipeline. CONCLUSIONS: VP343 has the properties of a good drug candidate and merits further investigations.
BACKGROUND: This study aimed to investigate compounds acting on the host cell machinery to impair parasite installation with the possible advantage of limiting drug resistance. The strategy therefore consisted of selecting compounds that are poorly active on the axenic parasite, but very active on the intramacrophage form of Leishmania. OBJECTIVES: To identify a drug candidate from focused screening of adamantamine derivatives that can inhibit the development of Leishmania infantum in macrophages. METHODS: In vitro screening was performed on a library of 142 adamantamine derivatives with axenic and intramacrophage forms of L. infantum, as well as cytotoxicity assays, allowing selection of the most promising compound. Absorption, distribution, metabolism and excretion (ADME) experiments, including pharmacokinetics and microsomal stability, were performed and finally the physicochemical stability of the compound was investigated to assess its suitability for further drug development. RESULTS:VP343 was identified first in vitro, with a CC50 value of 63.7 μM and an IC50 value of 0.32 μM for L. infantum intramacrophage amastigotes and then in vivo, with a 59% reduction of the liver parasite burden after oral administration at 10 mg/kg/day for 5 days. In addition, the ADME data were compatible with moving this compound further through the antileishmanial drug candidate pipeline. CONCLUSIONS:VP343 has the properties of a good drug candidate and merits further investigations.
Authors: Christina L Koumpoura; Michel Nguyen; Christian Bijani; Laure Vendier; Elena G Salina; Silvia Buroni; Giulia Degiacomi; Sandrine Cojean; Philippe M Loiseau; Françoise Benoit-Vical; Alfonso T García-Sosa; Michel Baltas Journal: ACS Omega Date: 2022-10-03
Authors: Saida Lachhab; Az-Eddine El Mansouri; Ahmad Mehdi; Indira Dennemont; Johan Neyts; Dirk Jochmans; Graciela Andrei; Robert Snoeck; Yogesh S Sanghvi; Mustapha Ait Ali; Philippe M Loiseau; Hassan B Lazrek Journal: Mol Divers Date: 2022-10-17 Impact factor: 3.364