Targeting Bacillus anthracis toxicity with a genetically selected inhibitor of the PA/CMG2 protein-protein interaction

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 librar...

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Autores principales:	Abigail L. Male, Fedor Forafonov, Francesco Cuda, Gong Zhang, Siqi Zheng, Petra C. F. Oyston, Peng R. Chen, E. Diane Williamson, Ali Tavassoli
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e4170e0bad4d42f1b4715b788d8d0feb
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spelling	oai:doaj.org-article:e4170e0bad4d42f1b4715b788d8d0feb2021-12-02T15:05:39ZTargeting Bacillus anthracis toxicity with a genetically selected inhibitor of the PA/CMG2 protein-protein interaction10.1038/s41598-017-03253-32045-2322https://doaj.org/article/e4170e0bad4d42f1b4715b788d8d0feb2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03253-3https://doaj.org/toc/2045-2322Abstract 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.Abigail L. MaleFedor ForafonovFrancesco CudaGong ZhangSiqi ZhengPetra C. F. OystonPeng R. ChenE. Diane WilliamsonAli TavassoliNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Abigail L. Male Fedor Forafonov Francesco Cuda Gong Zhang Siqi Zheng Petra C. F. Oyston Peng R. Chen E. Diane Williamson Ali Tavassoli Targeting Bacillus anthracis toxicity with a genetically selected inhibitor of the PA/CMG2 protein-protein interaction
description	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.
format	article
author	Abigail L. Male Fedor Forafonov Francesco Cuda Gong Zhang Siqi Zheng Petra C. F. Oyston Peng R. Chen E. Diane Williamson Ali Tavassoli
author_facet	Abigail L. Male Fedor Forafonov Francesco Cuda Gong Zhang Siqi Zheng Petra C. F. Oyston Peng R. Chen E. Diane Williamson Ali Tavassoli
author_sort	Abigail L. Male
title	Targeting Bacillus anthracis toxicity with a genetically selected inhibitor of the PA/CMG2 protein-protein interaction
title_short	Targeting Bacillus anthracis toxicity with a genetically selected inhibitor of the PA/CMG2 protein-protein interaction
title_full	Targeting Bacillus anthracis toxicity with a genetically selected inhibitor of the PA/CMG2 protein-protein interaction
title_fullStr	Targeting Bacillus anthracis toxicity with a genetically selected inhibitor of the PA/CMG2 protein-protein interaction
title_full_unstemmed	Targeting Bacillus anthracis toxicity with a genetically selected inhibitor of the PA/CMG2 protein-protein interaction
title_sort	targeting bacillus anthracis toxicity with a genetically selected inhibitor of the pa/cmg2 protein-protein interaction
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e4170e0bad4d42f1b4715b788d8d0feb
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Targeting Bacillus anthracis toxicity with a genetically selected inhibitor of the PA/CMG2 protein-protein interaction

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