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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
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.
2045-2322
Male, Abigail L.
cad6c2bc-04df-4078-b5d2-9f3c808e6152
Forafonov, Fedor
bbb38ccc-5f35-48ab-9e06-a8ab0f0aae37
Cuda, Francesco
ad509342-f3ce-4957-96aa-338007af1e41
Zhang, Gong
e4d41e77-72ee-4359-a39a-160297848f37
Zheng, siqi
70906de6-5238-45ee-bafa-19631973a2aa
Oyston, Petra C.F.
bba5dae5-b0ee-4733-b6bd-05866be64793
Chen, Peng R.
49fbb957-9358-4757-a662-f869292afd68
Williamson, E. Diane
bd91c757-419c-4caf-bca7-388b9ccd6714
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2
Male, Abigail L.
cad6c2bc-04df-4078-b5d2-9f3c808e6152
Forafonov, Fedor
bbb38ccc-5f35-48ab-9e06-a8ab0f0aae37
Cuda, Francesco
ad509342-f3ce-4957-96aa-338007af1e41
Zhang, Gong
e4d41e77-72ee-4359-a39a-160297848f37
Zheng, siqi
70906de6-5238-45ee-bafa-19631973a2aa
Oyston, Petra C.F.
bba5dae5-b0ee-4733-b6bd-05866be64793
Chen, Peng R.
49fbb957-9358-4757-a662-f869292afd68
Williamson, E. Diane
bd91c757-419c-4caf-bca7-388b9ccd6714
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2

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).

Record type: Article

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.

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Accepted/In Press date: 25 April 2017
e-pub ahead of print date: 8 June 2017
Organisations: CBDT

Identifiers

Local EPrints ID: 411250
URI: http://eprints.soton.ac.uk/id/eprint/411250
ISSN: 2045-2322
PURE UUID: da0e396c-68b6-4956-8446-d6b06b6e9704
ORCID for Ali Tavassoli: ORCID iD orcid.org/0000-0002-7420-5063

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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
Author: Ali Tavassoli ORCID iD

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