Novel small molecule inhibitors of botulinum neurotoxin A metalloprotease activity

James C. Burnett; James J. Schmidt; Robert G. Stafford; Rekha G. Panchal; Tam L. Nguyen; Ann R. Hermone; Jonathan L. Vennerstrom; Connor F. McGrath; Douglas J. Lane; Edward A. Sausville; Daniel W. Zaharevitz; Rick Gussio; Sina Bavari

doi:10.1016/j.bbrc.2003.08.112

Novel small molecule inhibitors of botulinum neurotoxin A metalloprotease activity

James C. Burnett, James J. Schmidt, Robert G. Stafford, Rekha G. Panchal, Tam L. Nguyen, Ann R. Hermone, Jonathan L. Vennerstrom, Connor F. McGrath, Douglas J. Lane, Edward A. Sausville, Daniel W. Zaharevitz, Rick Gussio, Sina Bavari

Pharmaceutical Science

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

95 Scopus citations

Abstract

Botulinum neurotoxins (BoNTs) are among the most lethal biological substances to have been weaponized and are listed as biodefense category A agents. Currently, no small molecule (non-peptidic) therapeutics exist to counter this threat; hence, identifying and developing compounds that inhibit BoNTs is a high priority. In the present study, a high-throughput assay was used to identify small molecules that inhibit the metalloprotease activity of BoNT serotype A light chain (BoNT/A LC). All inhibitors were further verified using a HPLC-based assay. Conformational analyses of these compounds, in conjunction with molecular docking studies, were used to predict structural features that contribute to inhibitor binding and potency. Based on these results, a common pharmacophore for BoNT/A LC inhibitors is proposed. This is the first study to report small molecules (non-peptidics) that inhibit BoNT/A LC metalloprotease activity in the low μM range.

Original language	English (US)
Pages (from-to)	84-93
Number of pages	10
Journal	Biochemical and Biophysical Research Communications
Volume	310
Issue number	1
DOIs	https://doi.org/10.1016/j.bbrc.2003.08.112
State	Published - Oct 10 2003

Keywords

Bioterrorism
Botulinum neurotoxin
Drug discovery
High-throughput screen
Inhibitors
Metalloprotease
Molecular modeling
Pharmacophore
Three-dimensional database search

ASJC Scopus subject areas

Biophysics
Biochemistry
Molecular Biology
Cell Biology

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Burnett, J. C., Schmidt, J. J., Stafford, R. G., Panchal, R. G., Nguyen, T. L., Hermone, A. R., Vennerstrom, J. L., McGrath, C. F., Lane, D. J., Sausville, E. A., Zaharevitz, D. W., Gussio, R., & Bavari, S. (2003). Novel small molecule inhibitors of botulinum neurotoxin A metalloprotease activity. Biochemical and Biophysical Research Communications, 310(1), 84-93. https://doi.org/10.1016/j.bbrc.2003.08.112

Burnett, JC, Schmidt, JJ, Stafford, RG, Panchal, RG, Nguyen, TL, Hermone, AR, Vennerstrom, JL, McGrath, CF, Lane, DJ, Sausville, EA, Zaharevitz, DW, Gussio, R & Bavari, S 2003, 'Novel small molecule inhibitors of botulinum neurotoxin A metalloprotease activity', Biochemical and Biophysical Research Communications, vol. 310, no. 1, pp. 84-93. https://doi.org/10.1016/j.bbrc.2003.08.112

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abstract = "Botulinum neurotoxins (BoNTs) are among the most lethal biological substances to have been weaponized and are listed as biodefense category A agents. Currently, no small molecule (non-peptidic) therapeutics exist to counter this threat; hence, identifying and developing compounds that inhibit BoNTs is a high priority. In the present study, a high-throughput assay was used to identify small molecules that inhibit the metalloprotease activity of BoNT serotype A light chain (BoNT/A LC). All inhibitors were further verified using a HPLC-based assay. Conformational analyses of these compounds, in conjunction with molecular docking studies, were used to predict structural features that contribute to inhibitor binding and potency. Based on these results, a common pharmacophore for BoNT/A LC inhibitors is proposed. This is the first study to report small molecules (non-peptidics) that inhibit BoNT/A LC metalloprotease activity in the low μM range.",

keywords = "Bioterrorism, Botulinum neurotoxin, Drug discovery, High-throughput screen, Inhibitors, Metalloprotease, Molecular modeling, Pharmacophore, Three-dimensional database search",

author = "Burnett, {James C.} and Schmidt, {James J.} and Stafford, {Robert G.} and Panchal, {Rekha G.} and Nguyen, {Tam L.} and Hermone, {Ann R.} and Vennerstrom, {Jonathan L.} and McGrath, {Connor F.} and Lane, {Douglas J.} and Sausville, {Edward A.} and Zaharevitz, {Daniel W.} and Rick Gussio and Sina Bavari",

note = "Funding Information: The research described herein was sponsored by the US Army Medical Research and Material Command Research Plan # 02-4-3U-057 and IAA # Y3-CM-100505 (MRMC and NCI). We acknowledge the National Cancer Institute for the allocation of computing time and staff support at the Advanced Biomedical Computing Center of the Frederick Cancer Research and Development Center. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the US Government. ",

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AU - Burnett, James C.

AU - Schmidt, James J.

AU - Stafford, Robert G.

AU - Panchal, Rekha G.

AU - Nguyen, Tam L.

AU - Hermone, Ann R.

AU - Vennerstrom, Jonathan L.

AU - McGrath, Connor F.

AU - Lane, Douglas J.

AU - Sausville, Edward A.

AU - Zaharevitz, Daniel W.

AU - Gussio, Rick

AU - Bavari, Sina

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N2 - Botulinum neurotoxins (BoNTs) are among the most lethal biological substances to have been weaponized and are listed as biodefense category A agents. Currently, no small molecule (non-peptidic) therapeutics exist to counter this threat; hence, identifying and developing compounds that inhibit BoNTs is a high priority. In the present study, a high-throughput assay was used to identify small molecules that inhibit the metalloprotease activity of BoNT serotype A light chain (BoNT/A LC). All inhibitors were further verified using a HPLC-based assay. Conformational analyses of these compounds, in conjunction with molecular docking studies, were used to predict structural features that contribute to inhibitor binding and potency. Based on these results, a common pharmacophore for BoNT/A LC inhibitors is proposed. This is the first study to report small molecules (non-peptidics) that inhibit BoNT/A LC metalloprotease activity in the low μM range.

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KW - High-throughput screen

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KW - Molecular modeling

KW - Pharmacophore

KW - Three-dimensional database search

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Novel small molecule inhibitors of botulinum neurotoxin A metalloprotease activity

Abstract

Keywords

ASJC Scopus subject areas

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