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

Bankala Krishnarjuna, San Sui Lim, Shane M Devine, Cael O Debono, Raymond Lam, Indu R Chandrashekaran, Garima Jaipuria, Hiromasa Yagi, Hanudatta S Atreya, Martin J Scanlon, Christopher A MacRaild, Peter J Scammells, Raymond S Norton

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)281-291
Number of pages11
JournalJournal of Molecular Recognition
Volume29
Issue number6
DOIs
Publication statusPublished - 1 Jun 2016

Keywords

  • AMA1
  • fragments
  • isotopic labelling
  • NMR
  • resonance assignments
  • SPR

Cite this

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title = "Solution NMR characterization of apical membrane antigen 1 and small molecule interactions as a basis for designing new antimalarials",
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.",
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author = "Bankala Krishnarjuna and Lim, {San Sui} and Devine, {Shane M} and Debono, {Cael O} and Raymond Lam and Chandrashekaran, {Indu R} and Garima Jaipuria and Hiromasa Yagi and Atreya, {Hanudatta S} and Scanlon, {Martin J} and MacRaild, {Christopher A} and Scammells, {Peter J} and Norton, {Raymond S}",
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AU - Krishnarjuna, Bankala

AU - Lim, San Sui

AU - Devine, Shane M

AU - Debono, Cael O

AU - Lam, Raymond

AU - Chandrashekaran, Indu R

AU - Jaipuria, Garima

AU - Yagi, Hiromasa

AU - Atreya, Hanudatta S

AU - Scanlon, Martin J

AU - MacRaild, Christopher A

AU - Scammells, Peter J

AU - Norton, Raymond S

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