title: Antiplasmodial activity study of angiotensin II via Ala scan analogs.
abstract: Angiotensin II (AII) as well as analog peptides shows antimalarial activity against Plasmodium gallinaceum and Plasmodium falciparum, but the exact mechanism of action is still unknown. This work presents the solid-phase synthesis and characterization of eight peptides corresponding to the alanine scanning series of AII plus the amide-capped derivative and the evaluation of the antiplasmodial activity of these peptides against mature P. gallinaceum sporozoites. The Ala screening data indicates that the replacement of either the Ile(5) or the His(6) residues causes minor effects on the in vitro antiplasmodial activity compared with AII, i.e. AII (88%), [Ala(6) ]-AII (79%), and [Ala(5) ]-AII (75%). Analogs [Ala(3) ]-AII, [Ala(1) ]-AII, and AII-NH2 showed antiplasmodial activity around 65%, whereas the activity of the [Ala(8) ]-AII, [Ala(7) ]-AII, [Ala(4) ]-AII, and [Ala(2) ]-AII analogs is lower than 45%. Circular dichroism data suggest that AII and the most active analogs adopt a β-fold conformation in different solutions. All AII analogs, except [Ala(4) ]-AII and [Ala(8) ]-AII, show contractile responses and interact with the AT1 receptor, [Ala(5) ]-AII and [Ala(6) ]-AII. In conclusion, this approach is helpful to understand the contribution of each amino acid residue to the bioactivity of AII, opening new perspectives toward the design of new sporozoiticidal compounds.
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, SP, Brazil.
authors.forename: Adriana Farias
authors.initials: AF
authors.lastname: Silva
authors.forename: Erick Leite
authors.initials: EL
authors.lastname: Bastos
authors.forename: Marcelo Der Torossian
authors.initials: MD
authors.lastname: Torres
authors.forename: André Luis
authors.initials: AL
authors.lastname: Costa-da-Silva
authors.forename: Rafaella Sayuri
authors.initials: RS
authors.lastname: Ioshino
authors.forename: Margareth Lara
authors.initials: ML
authors.lastname: Capurro
authors.forename: Flávio Lopes
authors.initials: FL
authors.lastname: Alves
authors.forename: Antonio
authors.initials: A
authors.lastname: Miranda
authors.forename: Renata de Freitas Fischer
authors.initials: Rde F
authors.lastname: Vieira
authors.forename: Vani Xavier
authors.initials: VX
authors.lastname: Oliveira
mesh_terms: D000330:Aedes / Q000382:microbiology; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D002645:Chickens; D002942:Circular Dichroism; D010455:Peptides / Q000138:chemical synthesis; D010964:Plasmodium gallinaceum / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects; D060327:Solid-Phase Synthesis Techniques
chemical_list: D000962:Antimalarials; D010455:Peptides; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II
keywords: Plasmodium gallinaceum; SPPS; angiotensin II; malaria; sporozoites; structure-activity relationship