Targeting Bacillus anthracis toxicity with a genetically selected inhibitor of the PA/CMG2 protein-protein interaction
Targeting Bacillus anthracis toxicity with a genetically selected inhibitor of the PA/CMG2 protein-protein interaction
The protein-protein interaction between the human CMG2 receptor and the Bacillus anthracis protective antigen (PA) is essential for the transport of anthrax lethal and edema toxins into human cells. We used a genetically encoded high throughput screening platform to screen a SICLOPPS library of 3.2 million cyclic hexapeptides for inhibitors of this protein-protein interaction. Unusually, the top 3 hits all contained stop codons in the randomized region of the library, resulting in linear rather than cyclic peptides. These peptides disrupted the targeted interaction in vitro; two act by binding to CMG2 while one binds PA. The efficacy of the most potent CMG2-binding inhibitor was improved through the incorporation of non-natural phenylalanine analogues. Cell based assays demonstrated that the optimized inhibitor protects macrophages from the toxicity of lethal factor.
Male, Abigail L.
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Forafonov, Fedor
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Cuda, Francesco
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Zhang, Gong
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Zheng, siqi
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Oyston, Petra C.F.
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Chen, Peng R.
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Williamson, E. Diane
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Tavassoli, Ali
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Male, Abigail L.
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Forafonov, Fedor
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Cuda, Francesco
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Zhang, Gong
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Zheng, siqi
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Oyston, Petra C.F.
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Chen, Peng R.
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Williamson, E. Diane
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Tavassoli, Ali
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Male, Abigail L., Forafonov, Fedor, Cuda, Francesco, Zhang, Gong, Zheng, siqi, Oyston, Petra C.F., Chen, Peng R., Williamson, E. Diane and Tavassoli, Ali
(2017)
Targeting Bacillus anthracis toxicity with a genetically selected inhibitor of the PA/CMG2 protein-protein interaction.
Scientific Reports, 7, [3104].
(doi:10.1038/s41598-017-03253-3).
Abstract
The protein-protein interaction between the human CMG2 receptor and the Bacillus anthracis protective antigen (PA) is essential for the transport of anthrax lethal and edema toxins into human cells. We used a genetically encoded high throughput screening platform to screen a SICLOPPS library of 3.2 million cyclic hexapeptides for inhibitors of this protein-protein interaction. Unusually, the top 3 hits all contained stop codons in the randomized region of the library, resulting in linear rather than cyclic peptides. These peptides disrupted the targeted interaction in vitro; two act by binding to CMG2 while one binds PA. The efficacy of the most potent CMG2-binding inhibitor was improved through the incorporation of non-natural phenylalanine analogues. Cell based assays demonstrated that the optimized inhibitor protects macrophages from the toxicity of lethal factor.
Text
art_10.1038_s41598-017-03253-3
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Accepted/In Press date: 25 April 2017
e-pub ahead of print date: 8 June 2017
Organisations:
CBDT
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Local EPrints ID: 411250
URI: http://eprints.soton.ac.uk/id/eprint/411250
ISSN: 2045-2322
PURE UUID: da0e396c-68b6-4956-8446-d6b06b6e9704
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Date deposited: 16 Jun 2017 16:31
Last modified: 16 Mar 2024 03:51
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Contributors
Author:
Abigail L. Male
Author:
Fedor Forafonov
Author:
Francesco Cuda
Author:
Gong Zhang
Author:
siqi Zheng
Author:
Petra C.F. Oyston
Author:
Peng R. Chen
Author:
E. Diane Williamson
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