title: Pentamidine is an antiparasitic and apoptotic drug that selectively modifies ubiquitin.
abstract: We have determined the cytotoxic properties of pentamidine isethionate (2) towards the promastigotes of the protozoan parasite Leishmania infantum. The leishmanicidal activity of 2 was 60 times higher after 72 h of incubation than that of cisplatin (4). The pentamidine salt 2 induced a higher amount of programmed cell death (PCD) than cisplatin, which is associated with inhibition of DNA synthesis and cell-cycle arrest in the G2/M phase. Circular dichroism (CD) data indicate that binding of 2 to calf-thymus DNA (CT-DNA) induces conformational changes in the DNA double helix, consistent with a B-->A transition. Moreover, the interaction of 2 with ubiquitin led to a 6% increase in the beta-sheet content of the protein as observed by CD spectroscopy. Fluorescence-spectroscopy studies agreed with the CD data, showing that the pentamidine portion of 2 induces a significant decrease in the fluorescence of the Ub residues Phe4 and Phe45 located on the beta-cluster of the molecule, but not of Tyr59 on the alpha-cluster. These data indicate that pentamidine specifically modifies the beta-cluster, i.e., the 'basic face' of ubiquitin. Our results suggest that the biochemical mechanism of action of pentamidine may be a consequence of its dual binding to DNA and proteins.
authors.affiliation: Departamento de Parasitología, Facultad de Farmacia, Universidad de la Laguna Tenerife, Spain.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Nguewa
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Fuertes
authors.forename: Victoria
authors.initials: V
authors.lastname: Cepeda
authors.forename: Salvador
authors.initials: S
authors.lastname: Iborra
authors.forename: Javier
authors.initials: J
authors.lastname: Carrión
authors.forename: Basilio
authors.initials: B
authors.lastname: Valladares
authors.forename: Carlos
authors.initials: C
authors.lastname: Alonso
authors.forename: José M
authors.initials: JM
authors.lastname: Pérez
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018314:Leishmania infantum / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D010419:Pentamidine / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D025801:Ubiquitin / Q000737:chemistry*
chemical_list: D000981:Antiprotozoal Agents; D025801:Ubiquitin; D010419:Pentamidine