Botulinum neurotoxins (BoNTs) represent one of the most serious bioterror threats to our national security. Secreted by spore forming bacteria Clostridium botulinum, baratii, and butyricium, BoNTs are responsible for the flaccid paralysis associated with botulism. Listed as category A biothreats by the CDC, BoNTs are the most toxic of biological toxins, are easily produced, and may be delivered by various routes including food spiking (solid and liquid) and aerosol dispersion. There are no therapeutics to counter BoNT induced paralysis once the enzyme has entered the neuronal cytosol - at this time the only treatment option is impractical mechanical ventilation in a critical care setting. The long-term objective of this project is to address this public health threat by developing potent small molecule, non-peptidic, inhibitors (SMNPIs) of BoNTs as therapeutics that will serve as both rescue agents and prophylactics.
Specific aims 1 - 3 of the proposal focus on translating our lead uM range SMNPIs of BoNT serotype A into low nM range SMNPIs that are effective in an animal model.
Specific aim 4 concentrates on identifying and developing SMNPIs of BoNT serotype B that are effective in a neuronal assay, and specific aim 5 covers the identification of SMNPIs of BoNT serotype E. Finally, under specific aim 6, we propose examining all identified and developed SMNPIs for broad spectrum inhibitory activity against more than one BoNT serotype. To achieve the project goals we combine three-dimensional pharmacophore-based methods and synthetic organic chemistry strategies. Specifically, such methods combine X-ray crystallography, in vitro and in vivo biological testing, molecular modeling and 3-D database mining, and organic chemistry to guide SMNPI discovery and optimization (i.e., good in vitro potencies, good ADMET profiles, reduced toxicities, and enhanced in vivo efficacies in an animal model).
Botulinum neurotoxins (BoNTs) are the most potent toxins on the planet and are capable of being used as bioterror devises. There is currently no therapeutic to counter the inevitable suffocation and certain death resulting from the paralysis induced by BoNT poisoning. We propose the use of therapeutically viable chemicals as drugs. Our proposal includes molecules that already possess activity against critical components of the BoNT intoxication process for two serotypes.
|Konstantinovi?, Jelena; Kiris, Erkan; Kota, Krishna P et al. (2018) New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model. J Med Chem 61:1595-1608|
|Huang, Hanxia; Konduru, Krishnamurthy; Solovena, Veronica et al. (2016) Therapeutic potential of the heme oxygenase-1 inducer hemin against Ebola virus infection. Curr Trends Immunol 17:117-123|
|Kane, Christopher D; Nuss, Jonathan E; Bavari, Sina (2015) Novel therapeutic uses and formulations of botulinum neurotoxins: a patent review (2012 - 2014). Expert Opin Ther Pat 25:675-90|
|Zhao, Minglei; Wu, Shenping; Zhou, Qiangjun et al. (2015) Mechanistic insights into the recycling machine of the SNARE complex. Nature 518:61-7|
|Dong, Yuxiang; Wang, Xiaofang; Cal, Monica et al. (2014) Activity of diimidazoline amides against African trypanosomiasis. Bioorg Med Chem Lett 24:944-8|
|Videnovi?, Milica; Opsenica, Dejan M; Burnett, James C et al. (2014) Second generation steroidal 4-aminoquinolines are potent, dual-target inhibitors of the botulinum neurotoxin serotype A metalloprotease and P. falciparum malaria. J Med Chem 57:4134-53|
|Kota, Krishna P; Soloveva, Veronica; Wanner, Laura M et al. (2014) A high content imaging assay for identification of Botulinum neurotoxin inhibitors. J Vis Exp :e51915|
|Kiris, Erkan; Kota, Krishna P; Burnett, James C et al. (2014) Recent developments in cell-based assays and stem cell technologies for botulinum neurotoxin research and drug discovery. Expert Rev Mol Diagn 14:153-68|
|Kiris, Erkan; Burnett, James C; Kane, Christopher D et al. (2014) Recent advances in botulinum neurotoxin inhibitor development. Curr Top Med Chem 14:2044-61|
|Opsenica, Igor M; Tot, Mikloš; Gomba, Laura et al. (2013) 4-Amino-7-chloroquinolines: probing ligand efficiency provides botulinum neurotoxin serotype A light chain inhibitors with significant antiprotozoal activity. J Med Chem 56:5860-71|
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