title: Evidences for the action mechanism of angiotensin II and its analogs on Plasmodium sporozoite membranes.
abstract: Malaria is an infectious disease responsible for approximately one million deaths annually. Oligopeptides such as angiotensin II (AII) and its analogs are known to have antimalarial effects against Plasmodium gallinaceum and Plasmodium falciparum. However, their mechanism of action is still not fully understood at the molecular level. In the work reported here, we investigated this issue by comparing the antimalarial activity of AII with that of (i) its diastereomer formed by only d-amino acids; (ii) its isomer with reversed sequence; and (iii) its analogs restricted by lactam bridges, the so-called VC5 peptides. Data from fluorescence spectroscopy indicated that the antiplasmodial activities of both all-D-AII and all-D-VC5 were as high as those of the related peptides AII and VC5, respectively. In contrast, retro-AII had no significant effect against P. gallinaceum. Conformational analysis by circular dichroism suggested that AII and its active analogs usually adopted a β-turn conformation in different solutions. In the presence of membrane-mimetic micelles, AII had also a β-turn conformation, while retro-AII was random. Molecular dynamics simulations demonstrated that the AII chains were slightly more bent than retro-AII at the surface of a model membrane. At the hydrophobic membrane interior, however, the retro-AII chain was severely coiled and rigid. AII was much more flexible and able to experience both straight and coiled conformations. We took it as an indication of the stronger ability of AII to interact with membrane headgroups and promote pore formation.
authors: Universidade Federal do ABC, Centro de Ciências Naturais e Humanas, Santo André, SP, Brazil.
authors: Marcelo Der Torossian
authors: MD
authors: Torres
authors: Universidade Federal do ABC, Centro de Ciências Naturais e Humanas, Santo André, SP, Brazil.
authors: Adriana Farias
authors: AF
authors: Silva
authors: Universidade Federal de São Paulo, Departamento de Biofísica, São Paulo, SP, Brazil.
authors: Flávio Lopes
authors: FL
authors: Alves
authors: Universidade de São Paulo, Instituto de Ciências Biomédicas II, São Paulo, SP, Brazil.
authors: Margareth Lara
authors: ML
authors: Capurro
authors: Universidade Federal de São Paulo, Departamento de Biofísica, São Paulo, SP, Brazil.
authors: Antonio
authors: A
authors: Miranda
authors: Universidade Federal do ABC, Centro de Ciências Naturais e Humanas, Santo André, SP, Brazil.
authors: Rodrigo Maghdissian
authors: RM
authors: Cordeiro
authors: Universidade Federal do ABC, Centro de Ciências Naturais e Humanas, Santo André, SP, Brazil.
authors: Vani Xavier
authors: VX
authors: Oliveira Junior
mesh_terms: D000330:Aedes / Q000469:parasitology; D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects*; D002645:Chickens; D008289:Malaria, Avian / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D008823:Micelles; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010964:Plasmodium gallinaceum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D012469:Salivary Glands / Q000469:parasitology; D060327:Solid-Phase Synthesis Techniques; D034101:Sporozoites / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D008823:Micelles; D010455:Peptides; D000804:Angiotensin II
keywords: Plasmodium; angiotensin II; malaria; molecular dynamics