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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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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Publication: | JOURNAL OF MOLECULAR RECOGNITION |
Publisher: | WILEY-BLACKWELL |
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 Sophisticated Instruments Facility) |
Date Deposited: | 25 Aug 2016 10:13 |
Last Modified: | 25 Aug 2016 10:13 |
URI: | http://eprints.iisc.ac.in/id/eprint/54335 |
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