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Solution NMR characterization of apical membrane antigen 1 and small molecule interactions as a basis for designing new antimalarials

Krishnarjuna, Bankala and Lim, San Sui and Devine, Shane M and Debono, Cael O and Lam, Raymond and Chandrashekaran, Indu R and Jaipuria, Garima and Yagi, Hiromasa and Atreya, Hanudatta S and Scanlon, Martin J and MacRaild, Christopher A and Scammells, Peter J and Norton, Raymond S (2016) Solution NMR characterization of apical membrane antigen 1 and small molecule interactions as a basis for designing new antimalarials. In: JOURNAL OF MOLECULAR RECOGNITION, 29 (6). pp. 281-291.

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Official URL: http://dx.doi.org/10.1002/jmr.2529

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 (C) 2016 John Wiley & Sons, Ltd.

Item Type: Journal Article
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Additional Information: Copy right for this article belongs to the WILEY-BLACKWELL, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
Keywords: AMA1; NMR; resonance assignments; isotopic labelling; SPR; fragments
Department/Centre: Division of Chemical Sciences > NMR Research Centre (Formerly SIF)
Date Deposited: 25 Aug 2016 10:13
Last Modified: 25 Aug 2016 10:13
URI: http://eprints.iisc.ernet.in/id/eprint/54335

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