Pharmacophore refinement guides the design of nanomolar-range botulinum neurotoxin serotype a light chain inhibitors

Jonathan E. Nuss; Yuxiang Dong; Laura M. Wanner; Gordon Ruthel; Peter Wipf; Rick Gussio; Jonathan L. Vennerstrom; Sina Bavari; James C. Burnett

doi:10.1021/ml100056v

Pharmacophore refinement guides the design of nanomolar-range botulinum neurotoxin serotype a light chain inhibitors

Jonathan E. Nuss, Yuxiang Dong, Laura M. Wanner, Gordon Ruthel, Peter Wipf, Rick Gussio, Jonathan L. Vennerstrom, Sina Bavari, James C. Burnett

Pharmaceutical Science

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

15 Scopus citations

Abstract

Botulinum neurotoxins (BoNTs) are the deadliest of microbial toxins. The enzymes' zinc(II) metalloprotease, referred to as the light chain (LC) component, inhibits acetylcholine release into neuromuscular junctions, resulting in the disease botulism. Currently, no therapies counter BoNT poisoning postneuronal intoxication; however, it is hypothesized that small molecules may be used to inhibit BoNT LC activity in the neuronal cytosol. Herein, we describe the pharmacophore-based design and chemical synthesis of potent [non-zinc(II) chelating] small molecule (nonpeptidic) inhibitors (SMNPIs) of the BoNT serotype A LC (the most toxic of the BoNT serotype LCs). Specifically, the three-dimensional superimpositions of 2-[4-(4-amidinephenoxy) phenyl]indole-6-amidine-based SMNPI regioisomers [K_i = 0.600 μM (±0.100 μM)], with a novel lead bis-[3-amide-5-(imidazolino)phenyl] terephthalamide (BAIPT)-based SMNPI [K_i = 8.52 μM (±0.53 μM)], resulted in a refined four-zone pharmacophore. The refined model guided the design of BAIPT-based SMNPIs possessing K_i values = 0.572 (±0.041 μM) and 0.900 μM (±0.078 μM).

Original language	English (US)
Pages (from-to)	301-305
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	1
Issue number	7
DOIs	https://doi.org/10.1021/ml100056v
State	Published - Oct 14 2010

Keywords

Botulinum neurotoxin
biothreat agent
gas-phase pharmacophore
rational design
small molecule inhibitor

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/ml100056v

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title = "Pharmacophore refinement guides the design of nanomolar-range botulinum neurotoxin serotype a light chain inhibitors",

abstract = "Botulinum neurotoxins (BoNTs) are the deadliest of microbial toxins. The enzymes' zinc(II) metalloprotease, referred to as the light chain (LC) component, inhibits acetylcholine release into neuromuscular junctions, resulting in the disease botulism. Currently, no therapies counter BoNT poisoning postneuronal intoxication; however, it is hypothesized that small molecules may be used to inhibit BoNT LC activity in the neuronal cytosol. Herein, we describe the pharmacophore-based design and chemical synthesis of potent [non-zinc(II) chelating] small molecule (nonpeptidic) inhibitors (SMNPIs) of the BoNT serotype A LC (the most toxic of the BoNT serotype LCs). Specifically, the three-dimensional superimpositions of 2-[4-(4-amidinephenoxy) phenyl]indole-6-amidine-based SMNPI regioisomers [Ki = 0.600 μM (±0.100 μM)], with a novel lead bis-[3-amide-5-(imidazolino)phenyl] terephthalamide (BAIPT)-based SMNPI [Ki = 8.52 μM (±0.53 μM)], resulted in a refined four-zone pharmacophore. The refined model guided the design of BAIPT-based SMNPIs possessing Ki values = 0.572 (±0.041 μM) and 0.900 μM (±0.078 μM).",

keywords = "Botulinum neurotoxin, biothreat agent, gas-phase pharmacophore, rational design, small molecule inhibitor",

author = "Nuss, {Jonathan E.} and Yuxiang Dong and Wanner, {Laura M.} and Gordon Ruthel and Peter Wipf and Rick Gussio and Vennerstrom, {Jonathan L.} and Sina Bavari and Burnett, {James C.}",

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AU - Nuss, Jonathan E.

AU - Dong, Yuxiang

AU - Wanner, Laura M.

AU - Ruthel, Gordon

AU - Wipf, Peter

AU - Gussio, Rick

AU - Vennerstrom, Jonathan L.

AU - Bavari, Sina

AU - Burnett, James C.

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N2 - Botulinum neurotoxins (BoNTs) are the deadliest of microbial toxins. The enzymes' zinc(II) metalloprotease, referred to as the light chain (LC) component, inhibits acetylcholine release into neuromuscular junctions, resulting in the disease botulism. Currently, no therapies counter BoNT poisoning postneuronal intoxication; however, it is hypothesized that small molecules may be used to inhibit BoNT LC activity in the neuronal cytosol. Herein, we describe the pharmacophore-based design and chemical synthesis of potent [non-zinc(II) chelating] small molecule (nonpeptidic) inhibitors (SMNPIs) of the BoNT serotype A LC (the most toxic of the BoNT serotype LCs). Specifically, the three-dimensional superimpositions of 2-[4-(4-amidinephenoxy) phenyl]indole-6-amidine-based SMNPI regioisomers [Ki = 0.600 μM (±0.100 μM)], with a novel lead bis-[3-amide-5-(imidazolino)phenyl] terephthalamide (BAIPT)-based SMNPI [Ki = 8.52 μM (±0.53 μM)], resulted in a refined four-zone pharmacophore. The refined model guided the design of BAIPT-based SMNPIs possessing Ki values = 0.572 (±0.041 μM) and 0.900 μM (±0.078 μM).

AB - Botulinum neurotoxins (BoNTs) are the deadliest of microbial toxins. The enzymes' zinc(II) metalloprotease, referred to as the light chain (LC) component, inhibits acetylcholine release into neuromuscular junctions, resulting in the disease botulism. Currently, no therapies counter BoNT poisoning postneuronal intoxication; however, it is hypothesized that small molecules may be used to inhibit BoNT LC activity in the neuronal cytosol. Herein, we describe the pharmacophore-based design and chemical synthesis of potent [non-zinc(II) chelating] small molecule (nonpeptidic) inhibitors (SMNPIs) of the BoNT serotype A LC (the most toxic of the BoNT serotype LCs). Specifically, the three-dimensional superimpositions of 2-[4-(4-amidinephenoxy) phenyl]indole-6-amidine-based SMNPI regioisomers [Ki = 0.600 μM (±0.100 μM)], with a novel lead bis-[3-amide-5-(imidazolino)phenyl] terephthalamide (BAIPT)-based SMNPI [Ki = 8.52 μM (±0.53 μM)], resulted in a refined four-zone pharmacophore. The refined model guided the design of BAIPT-based SMNPIs possessing Ki values = 0.572 (±0.041 μM) and 0.900 μM (±0.078 μM).

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Pharmacophore refinement guides the design of nanomolar-range botulinum neurotoxin serotype a light chain inhibitors

Abstract

Keywords

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