Solution NMR characterization of apical membrane antigen 1 and small molecule interactions as a basis for designing new antimalarials.
J Mol Recognit
; 29(6): 281-91, 2016 06.
Article
em En
| MEDLINE
| ID: mdl-26804042
ABSTRACT
Plasmodium falciparum apical membrane antigen 1 (PfAMA1) plays an important role in the invasion by merozoites of human red blood cells during a malaria infection. A key region of PfAMA1 is a conserved hydrophobic cleft formed by 12 hydrophobic residues. As anti-apical membrane antigen 1 antibodies and other inhibitory molecules that target this hydrophobic cleft are able to block the invasion process, PfAMA1 is an attractive target for the development of strain-transcending antimalarial agents. As solution nuclear magnetic resonance spectroscopy is a valuable technique for the rapid characterization of protein-ligand interactions, we have determined the sequence-specific backbone assignments for PfAMA1 from two P. falciparum strains, FVO and 3D7. Both selective labelling and unlabelling strategies were used to complement triple-resonance experiments in order to facilitate the assignment process. We have then used these assignments for mapping the binding sites for small molecules, including benzimidazoles, pyrazoles and 2-aminothiazoles, which were selected on the basis of their affinities measured from surface plasmon resonance binding experiments. Among the compounds tested, benzimidazoles showed binding to a similar region on both FVO and 3D7 PfAMA1, suggesting that these compounds are promising scaffolds for the development of novel PfAMA1 inhibitors. Copyright © 2016 John Wiley & Sons, Ltd.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Plasmodium falciparum
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Proteínas de Protozoários
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Bibliotecas de Moléculas Pequenas
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Proteínas de Membrana
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Antígenos de Protozoários
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Antimaláricos
Limite:
Humans
Idioma:
En
Revista:
J Mol Recognit
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Austrália