title: Enhanced leishmanicidal activity of cryptopeptide chimeras from the active N1 domain of bovine lactoferrin.
abstract: Two antimicrobial cryptopeptides from the N1 domain of bovine lactoferrin, lactoferricin (LFcin17-30) and lactoferrampin (LFampin265-284), together with a hybrid version (LFchimera), were tested against the protozoan parasite Leishmania. All peptides were leishmanicidal against Leishmania donovani promastigotes, and LFchimera showed a significantly higher activity over its two composing moieties. Besides, it was the only peptide active on Leishmania pifanoi axenic amastigotes, already showing activity below 10 μM. To investigate their leishmanicidal mechanism, promastigote membrane permeabilization was assessed by decrease of free ATP levels in living parasites, entrance of the vital dye SYTOX Green (MW = 600 Da) and confocal and transmission electron microscopy. The peptides induced plasma membrane permeabilization and bioenergetic collapse of the parasites. To further clarify the structural traits underlying the increased leishmanicidal activity of LFchimera, the activity of several analogues was assessed. Results revealed that the high activity of these hybrid peptides seems to be related to the order and sequence orientation of the two cryptopeptide moieties, rather than to their particular linkage through an additional lysine, as in the initial LFchimera. The incorporation of both antimicrobial cryptopeptide motifs into a single linear sequence facilitates chemical synthesis and should help in the potential clinical application of these optimized analogues.
authors.affiliation: Departamento de Química e Bioquímica, Faculdade de Ciências, Centro Investigação em Química CIQ(UP), Universidade do Porto, Rua do Campo Alegre, 4169-007, Porto, Portugal.
authors.forename: Tânia
authors.initials: T
authors.lastname: Silva
authors.forename: María Ángeles
authors.initials: MÁ
authors.lastname: Abengózar
authors.forename: María
authors.initials: M
authors.lastname: Fernández-Reyes
authors.forename: David
authors.initials: D
authors.lastname: Andreu
authors.forename: Kamran
authors.initials: K
authors.lastname: Nazmi
authors.forename: Jan G M
authors.initials: JG
authors.lastname: Bolscher
authors.forename: Margarida
authors.initials: M
authors.lastname: Bastos
authors.forename: Luis
authors.initials: L
authors.lastname: Rivas
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D007781:Lactoferrin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007893:Leishmania donovani / Q000187:drug effects*; D008958:Models, Molecular; D021261:Parasitic Sensitivity Tests; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D010446:Peptide Fragments; C502040:lactoferrampin; C082171:lactoferricin B; D007781:Lactoferrin