Novel small molecule inhibitors of botulinum neurotoxin A metalloprotease activity
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...
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| Veröffentlicht in: | Biochemical and biophysical research communications 2003-10, Vol.310 (1), p.84-93 |
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| creator | Burnett, James C Schmidt, James J Stafford, Robert G Panchal, Rekha G Nguyen, Tam L Hermone, Ann R Vennerstrom, Jonathan L McGrath, Connor F Lane, Douglas J Sausville, Edward A Zaharevitz, Daniel W Gussio, Rick Bavari, Sina |
| description | 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. |
| doi_str_mv | 10.1016/j.bbrc.2003.08.112 |
| format | Article |
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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. 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This is the first study to report small molecules (non-peptidics) that inhibit BoNT/A LC metalloprotease activity in the low μM range.</description><subject>Bioterrorism</subject><subject>Botulinum neurotoxin</subject><subject>Botulinum Toxins - antagonists & inhibitors</subject><subject>Drug discovery</subject><subject>High-throughput screen</subject><subject>Inhibitors</subject><subject>Metalloprotease</subject><subject>Metalloproteases - antagonists & inhibitors</subject><subject>Molecular modeling</subject><subject>Pharmacophore</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Three-dimensional database search</subject><issn>0006-291X</issn><issn>1090-2104</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1LxDAQhoMo7vrxBzxITt5aZ9JuP8CLiF8gCqLgLTTpFLOkjSbp4v57u-yCN08Dw_O-zDyMnSGkCFhcLlOlvE4FQJZClSKKPTZHqCERCPk-mwNAkYgaP2bsKIQlAGJe1IdshvkCsViIOXt9diuyPPSNtbx3lvRoiZvh0ygTnQ_cdVy5OFozjD0faPQuuh8z8GveU5xC7mvaUBOINzqalYnrE3bQNTbQ6W4es_e727ebh-Tp5f7x5vop0bkoY6I05CqvsBUiFw20AspO6FKQQCpatTmPdKlzLEABFR10VZkJXSvVtVWbQXbMLra90wXfI4UoexM0WdsM5MYgsa4wW4hsAsUW1N6F4KmTX970jV9LBLkxKZdyY1JuTEqo5GRyCp3v2kfVU_sX2ambgKstQNOPK0NeBm1o0NQaTzrK1pn_-n8BH1GF9Q</recordid><startdate>20031010</startdate><enddate>20031010</enddate><creator>Burnett, James C</creator><creator>Schmidt, James J</creator><creator>Stafford, Robert G</creator><creator>Panchal, Rekha G</creator><creator>Nguyen, Tam L</creator><creator>Hermone, Ann R</creator><creator>Vennerstrom, Jonathan L</creator><creator>McGrath, Connor F</creator><creator>Lane, Douglas J</creator><creator>Sausville, Edward A</creator><creator>Zaharevitz, Daniel W</creator><creator>Gussio, Rick</creator><creator>Bavari, Sina</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7U7</scope><scope>C1K</scope></search><sort><creationdate>20031010</creationdate><title>Novel small molecule inhibitors of botulinum neurotoxin A metalloprotease activity</title><author>Burnett, James C ; 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| subjects | Bioterrorism Botulinum neurotoxin Botulinum Toxins - antagonists & inhibitors Drug discovery High-throughput screen Inhibitors Metalloprotease Metalloproteases - antagonists & inhibitors Molecular modeling Pharmacophore Protease Inhibitors - pharmacology Three-dimensional database search |
| title | Novel small molecule inhibitors of botulinum neurotoxin A metalloprotease activity |
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