Structure–activity studies of β-hairpin peptide inhibitors of the Plasmodium falciparum AMA1–RON2 interaction

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The interaction between apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2) plays a key role in the invasion of red blood cells by Plasmodium parasites. Disruption of this critical protein–protein interaction represents a promising avenue for antimalarial drug discovery. In this work, we exploited a 13-residue β-hairpin based on the C-terminal loop of RON2 to probe a conserved binding site on Plasmodium falciparum AMA1. A series of mutations was synthetically engineered into β-hairpin peptides to establish structure–activity relationships. The best mutations improved the binding affinity of the β-hairpin peptide by ~ 7-fold for 3D7 AMA1 and ~ 14-fold for FVO AMA1. We determined the crystal structures of several β-hairpin peptides in complex with AMA1 in order to define the structural features and specific interactions that contribute to improved binding affinity. The same mutations in the longer RON2sp2 peptide (residues 2027–2055 of RON2) increased the binding affinity by > 30-fold for 3D7 and FVO AMA1, producing KD values of 2.1 nM and 0.4 nM, respectively. To our knowledge, this is the most potent strain-transcending peptide reported to date and represents a valuable tool to characterize the AMA1–RON2 interaction.

Original languageEnglish
Pages (from-to)3986-3998
Number of pages13
JournalJournal of Molecular Biology
Volume428
Issue number20
DOIs
Publication statusPublished - 9 Oct 2016

Keywords

  • apical membrane antigen 1
  • malaria
  • peptide inhibitors
  • protein–peptide complex
  • structure-based ligand design

Cite this

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title = "Structure–activity studies of β-hairpin peptide inhibitors of the Plasmodium falciparum AMA1–RON2 interaction",
abstract = "The interaction between apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2) plays a key role in the invasion of red blood cells by Plasmodium parasites. Disruption of this critical protein–protein interaction represents a promising avenue for antimalarial drug discovery. In this work, we exploited a 13-residue β-hairpin based on the C-terminal loop of RON2 to probe a conserved binding site on Plasmodium falciparum AMA1. A series of mutations was synthetically engineered into β-hairpin peptides to establish structure–activity relationships. The best mutations improved the binding affinity of the β-hairpin peptide by ~ 7-fold for 3D7 AMA1 and ~ 14-fold for FVO AMA1. We determined the crystal structures of several β-hairpin peptides in complex with AMA1 in order to define the structural features and specific interactions that contribute to improved binding affinity. The same mutations in the longer RON2sp2 peptide (residues 2027–2055 of RON2) increased the binding affinity by > 30-fold for 3D7 and FVO AMA1, producing KD values of 2.1 nM and 0.4 nM, respectively. To our knowledge, this is the most potent strain-transcending peptide reported to date and represents a valuable tool to characterize the AMA1–RON2 interaction.",
keywords = "apical membrane antigen 1, malaria, peptide inhibitors, protein–peptide complex, structure-based ligand design",
author = "Geqing Wang and Nyssa Drinkwater and Drew, {Damien R.} and MacRaild, {Christopher A.} and Chalmers, {David K.} and Biswaranjan Mohanty and Lim, {San Sui} and Anders, {Robin F.} and Beeson, {James G.} and Thompson, {Philip E.} and Sheena McGowan and Simpson, {Jamie S.} and Norton, {Raymond S.} and Scanlon, {Martin J.}",
year = "2016",
month = "10",
day = "9",
doi = "10.1016/j.jmb.2016.07.001",
language = "English",
volume = "428",
pages = "3986--3998",
journal = "Journal of Molecular Biology",
issn = "0022-2836",
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Structure–activity studies of β-hairpin peptide inhibitors of the Plasmodium falciparum AMA1–RON2 interaction. / Wang, Geqing; Drinkwater, Nyssa; Drew, Damien R.; MacRaild, Christopher A.; Chalmers, David K.; Mohanty, Biswaranjan; Lim, San Sui; Anders, Robin F.; Beeson, James G.; Thompson, Philip E.; McGowan, Sheena; Simpson, Jamie S.; Norton, Raymond S.; Scanlon, Martin J.

In: Journal of Molecular Biology, Vol. 428, No. 20, 09.10.2016, p. 3986-3998.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Structure–activity studies of β-hairpin peptide inhibitors of the Plasmodium falciparum AMA1–RON2 interaction

AU - Wang, Geqing

AU - Drinkwater, Nyssa

AU - Drew, Damien R.

AU - MacRaild, Christopher A.

AU - Chalmers, David K.

AU - Mohanty, Biswaranjan

AU - Lim, San Sui

AU - Anders, Robin F.

AU - Beeson, James G.

AU - Thompson, Philip E.

AU - McGowan, Sheena

AU - Simpson, Jamie S.

AU - Norton, Raymond S.

AU - Scanlon, Martin J.

PY - 2016/10/9

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N2 - The interaction between apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2) plays a key role in the invasion of red blood cells by Plasmodium parasites. Disruption of this critical protein–protein interaction represents a promising avenue for antimalarial drug discovery. In this work, we exploited a 13-residue β-hairpin based on the C-terminal loop of RON2 to probe a conserved binding site on Plasmodium falciparum AMA1. A series of mutations was synthetically engineered into β-hairpin peptides to establish structure–activity relationships. The best mutations improved the binding affinity of the β-hairpin peptide by ~ 7-fold for 3D7 AMA1 and ~ 14-fold for FVO AMA1. We determined the crystal structures of several β-hairpin peptides in complex with AMA1 in order to define the structural features and specific interactions that contribute to improved binding affinity. The same mutations in the longer RON2sp2 peptide (residues 2027–2055 of RON2) increased the binding affinity by > 30-fold for 3D7 and FVO AMA1, producing KD values of 2.1 nM and 0.4 nM, respectively. To our knowledge, this is the most potent strain-transcending peptide reported to date and represents a valuable tool to characterize the AMA1–RON2 interaction.

AB - The interaction between apical membrane antigen 1 (AMA1) and rhoptry neck protein 2 (RON2) plays a key role in the invasion of red blood cells by Plasmodium parasites. Disruption of this critical protein–protein interaction represents a promising avenue for antimalarial drug discovery. In this work, we exploited a 13-residue β-hairpin based on the C-terminal loop of RON2 to probe a conserved binding site on Plasmodium falciparum AMA1. A series of mutations was synthetically engineered into β-hairpin peptides to establish structure–activity relationships. The best mutations improved the binding affinity of the β-hairpin peptide by ~ 7-fold for 3D7 AMA1 and ~ 14-fold for FVO AMA1. We determined the crystal structures of several β-hairpin peptides in complex with AMA1 in order to define the structural features and specific interactions that contribute to improved binding affinity. The same mutations in the longer RON2sp2 peptide (residues 2027–2055 of RON2) increased the binding affinity by > 30-fold for 3D7 and FVO AMA1, producing KD values of 2.1 nM and 0.4 nM, respectively. To our knowledge, this is the most potent strain-transcending peptide reported to date and represents a valuable tool to characterize the AMA1–RON2 interaction.

KW - apical membrane antigen 1

KW - malaria

KW - peptide inhibitors

KW - protein–peptide complex

KW - structure-based ligand design

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DO - 10.1016/j.jmb.2016.07.001

M3 - Article

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JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

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