Efficient synthetic inhibitors of anthrax lethal factor

Martino Forino; Sherida Johnson; Thiang Y. Wong; Dmitri V. Rozanov; Alexei Y. Savinov; Wei Li; Roberto Fattorusso; Barbara Becattini; Andrew J. Orry; Dawoon Jung; Ruben A. Abagyan; Jeffrey W. Smith; Ken Alibek; Robert C. Liddington; Alex Y. Strongin; Maurizio Pellecchia

doi:10.1073/pnas.0502733102

Efficient synthetic inhibitors of anthrax lethal factor

Martino Forino, Sherida Johnson, Thiang Y. Wong, Dmitri V. Rozanov, Alexei Y. Savinov, Wei Li, Roberto Fattorusso, Barbara Becattini, Andrew J. Orry, Dawoon Jung, Ruben A. Abagyan, Jeffrey W. Smith, Ken Alibek, Robert C. Liddington, Alex Y. Strongin, Maurizio Pellecchia

Research output: Contribution to journal › Article › peer-review

126 Scopus citations

Abstract

Inhalation anthrax is a deadly disease for which there is currently no effective treatment. Bacillus anthracis lethal factor (LF) metalloproteinase is an integral component of the tripartite anthrax lethal toxin that is essential for the onset and progression of anthrax. We report here on a fragment-based approach that allowed us to develop inhibitors of LF. The small-molecule inhibitors we have designed, synthesized, and tested are highly potent and selective against LF in both in vitro tests and cell-based assays. These inhibitors do not affect the prototype human metalloproteinases that are structurally similar to LF. Initial in vivo evaluation of postexposure efficacy of our inhibitors combined with antibiotic ciprofloxican against B. anthracis resulted in significant protection. Our data strongly indicate that the scaffold of inhibitors we have identified is the foundation for the development of novel, safe, and effective emergency therapy of postexposure inhalation anthrax.

Original language	English (US)
Pages (from-to)	9499-9504
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	102
Issue number	27
DOIs	https://doi.org/10.1073/pnas.0502733102
State	Published - Jul 5 2005
Externally published	Yes

Keywords

Drug design
Fragment-based design
Metalloprotease
NMR
Protective antigen

ASJC Scopus subject areas

General

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10.1073/pnas.0502733102

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Forino, M., Johnson, S., Wong, T. Y., Rozanov, D. V., Savinov, A. Y., Li, W., Fattorusso, R., Becattini, B., Orry, A. J., Jung, D., Abagyan, R. A., Smith, J. W., Alibek, K., Liddington, R. C., Strongin, A. Y., & Pellecchia, M. (2005). Efficient synthetic inhibitors of anthrax lethal factor. Proceedings of the National Academy of Sciences of the United States of America, 102(27), 9499-9504. https://doi.org/10.1073/pnas.0502733102

Forino, M, Johnson, S, Wong, TY, Rozanov, DV, Savinov, AY, Li, W, Fattorusso, R, Becattini, B, Orry, AJ, Jung, D, Abagyan, RA, Smith, JW, Alibek, K, Liddington, RC, Strongin, AY & Pellecchia, M 2005, 'Efficient synthetic inhibitors of anthrax lethal factor', Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 27, pp. 9499-9504. https://doi.org/10.1073/pnas.0502733102

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abstract = "Inhalation anthrax is a deadly disease for which there is currently no effective treatment. Bacillus anthracis lethal factor (LF) metalloproteinase is an integral component of the tripartite anthrax lethal toxin that is essential for the onset and progression of anthrax. We report here on a fragment-based approach that allowed us to develop inhibitors of LF. The small-molecule inhibitors we have designed, synthesized, and tested are highly potent and selective against LF in both in vitro tests and cell-based assays. These inhibitors do not affect the prototype human metalloproteinases that are structurally similar to LF. Initial in vivo evaluation of postexposure efficacy of our inhibitors combined with antibiotic ciprofloxican against B. anthracis resulted in significant protection. Our data strongly indicate that the scaffold of inhibitors we have identified is the foundation for the development of novel, safe, and effective emergency therapy of postexposure inhalation anthrax.",

keywords = "Drug design, Fragment-based design, Metalloprotease, NMR, Protective antigen",

author = "Martino Forino and Sherida Johnson and Wong, {Thiang Y.} and Rozanov, {Dmitri V.} and Savinov, {Alexei Y.} and Wei Li and Roberto Fattorusso and Barbara Becattini and Orry, {Andrew J.} and Dawoon Jung and Abagyan, {Ruben A.} and Smith, {Jeffrey W.} and Ken Alibek and Liddington, {Robert C.} and Strongin, {Alex Y.} and Maurizio Pellecchia",

note = "Funding Information: This work was financially supported in part by grants from the Swedish Board for Technical Development, (STU) and Imperial Chemical Industries (I.C.I.), PLC, U.K. One of us (B. L.) is grateful to Dr. Russell Ross for valuable discussions.",

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AU - Li, Wei

AU - Fattorusso, Roberto

AU - Becattini, Barbara

AU - Orry, Andrew J.

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AU - Abagyan, Ruben A.

AU - Smith, Jeffrey W.

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AU - Liddington, Robert C.

AU - Strongin, Alex Y.

AU - Pellecchia, Maurizio

N1 - Funding Information: This work was financially supported in part by grants from the Swedish Board for Technical Development, (STU) and Imperial Chemical Industries (I.C.I.), PLC, U.K. One of us (B. L.) is grateful to Dr. Russell Ross for valuable discussions.

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N2 - Inhalation anthrax is a deadly disease for which there is currently no effective treatment. Bacillus anthracis lethal factor (LF) metalloproteinase is an integral component of the tripartite anthrax lethal toxin that is essential for the onset and progression of anthrax. We report here on a fragment-based approach that allowed us to develop inhibitors of LF. The small-molecule inhibitors we have designed, synthesized, and tested are highly potent and selective against LF in both in vitro tests and cell-based assays. These inhibitors do not affect the prototype human metalloproteinases that are structurally similar to LF. Initial in vivo evaluation of postexposure efficacy of our inhibitors combined with antibiotic ciprofloxican against B. anthracis resulted in significant protection. Our data strongly indicate that the scaffold of inhibitors we have identified is the foundation for the development of novel, safe, and effective emergency therapy of postexposure inhalation anthrax.

AB - Inhalation anthrax is a deadly disease for which there is currently no effective treatment. Bacillus anthracis lethal factor (LF) metalloproteinase is an integral component of the tripartite anthrax lethal toxin that is essential for the onset and progression of anthrax. We report here on a fragment-based approach that allowed us to develop inhibitors of LF. The small-molecule inhibitors we have designed, synthesized, and tested are highly potent and selective against LF in both in vitro tests and cell-based assays. These inhibitors do not affect the prototype human metalloproteinases that are structurally similar to LF. Initial in vivo evaluation of postexposure efficacy of our inhibitors combined with antibiotic ciprofloxican against B. anthracis resulted in significant protection. Our data strongly indicate that the scaffold of inhibitors we have identified is the foundation for the development of novel, safe, and effective emergency therapy of postexposure inhalation anthrax.

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KW - NMR

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Efficient synthetic inhibitors of anthrax lethal factor

Abstract

Keywords

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