Small-molecule botulinum toxin inhibitors
Inventors
Pang, Yuan-Ping • Park, Jewn Giew • Tang, Jing • Millard, Charles B. • Schmidt, James J.
Assignees
Mayo Foundation for Medical Education and Research • United States Department of the Army • Government of the United States of America
Publication Number
US-8492428-B2
Publication Date
2013-07-23
Expiration Date
2026-09-20
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Small-molecule inhibitors of Botulinum toxin, including BoNTA, BoNTD and BoNTE are provided, as well as methods of using the inhibitors.
Core Innovation
This invention provides small-molecule inhibitors targeting Botulinum neurotoxin serotypes A, D, and E (BoNTA, BoNTD, and BoNTE). Specifically, these inhibitors act on the zinc endopeptidase domain of these toxins to inhibit their protease activity. The compounds are designed based on molecular modeling of the zinc coordination site, employing the cationic dummy atom (CaDA) approach to simulate zinc binding and optimize small molecules capable of coordinating the zinc ion in the active site.
The invention also provides methods of using these small-molecule inhibitors to treat, prevent, or ameliorate symptoms of Botulinum poisoning, including food-borne botulism and poisoning by BoNTA, BoNTD, or BoNTE. Compositions including compounds of Formula I, II, III, and IV are disclosed, along with pharmaceutical compositions, kits, and articles of manufacture containing these compounds. Administration can be through various routes, and the inhibitors can be combined with other treatments like trivalent equine antitoxin or penicillin G.
The problem being solved arises from the high toxicity of BoNTA, which inhibits acetylcholine release at neuromuscular junctions, leading to paralysis and death by respiratory arrest. While BoNTA is used medically and cosmetically, no chemical antidotes currently exist to counteract its toxic effects. This disclosure addresses the lack of chemical agents capable of inhibiting BoNTA and related serotypes' protease activity, offering a therapeutic avenue for Botulinum neurotoxin poisoning.
Claims Coverage
The patent claims encompass compositions containing small-molecule compounds according to specific chemical Formula I and related formulas, methods of treatment of Botulinum toxin poisoning using these compounds, methods for inhibiting zinc protease activity of BoNTA, BoNTD, and BoNTE, as well as kits and articles of manufacture comprising these compositions. Four main inventive features are identified from the independent claims.
Composition comprising compounds of Formula I
A composition comprising a compound according to Formula I characterized by specific chemical groups such as W (e.g., H, OH, NH2, or C1-C4 alkyl), Y (notably the hydroxamate group C(═O)NHOH), presence of sulfur (X2=S), and substituent groups Z including alkyl chains with amine moieties. The that compounds have defined structural parameters including heteroatoms and aromatic systems as listed in the formulas, and include pharmaceutically acceptable salts thereof.
Methods of treating Botulinum toxin poisoning using the compounds
Methods of treating or ameliorating symptoms associated with Botulinum toxin poisoning comprising administration of the compositions containing compounds of Formula I or their pharmaceutically acceptable salts to a mammal, including humans. The methods cover treatment of poisoning by BoNTA, BoNTD, or BoNTE, and may be combined with administration of trivalent equine antitoxin or penicillin G.
Methods for inhibiting zinc protease activity of Botulinum neurotoxins
A method for inhibiting the zinc protease activity of Botulinum neurotoxins (BoNTA, BoNTD, or BoNTE) by contacting the zinc protease with a compound of Formula I. This includes direct inhibition of the zinc endopeptidase responsible for toxin effects.
Kits and articles of manufacture comprising the compositions
Kits containing the composition of Formula I, including injectable forms, and articles of manufacture where the composition is disposed within pills, tablets, capsules, or syringes, designed for treating or ameliorating Botulinum toxin poisoning.
The independent claims focus on a chemical composition of novel small molecules targeting the zinc endopeptidase of Botulinum neurotoxins, methods of treatment of Botulinum toxin poisoning using these compositions, methods for enzymatic inhibition, as well as pharmaceutical kits and formulations comprising the compounds. These inventive features collectively provide a comprehensive framework for usage and manufacture of these inhibitors.
Stated Advantages
Potent and serotype-specific inhibition of BoNTA zinc endopeptidase activity, demonstrated by compounds such as compound 12 and analogs including 30a, 30b, 30k, and 30m.
Improved selectivity for BoNTA over BoNTB despite close structural relations, avoiding indiscriminate inhibition.
Ability to protect primary cholinergic neurons from the deleterious effects of BoNTA in cell culture assays, indicating therapeutic potential.
Applicability of the CaDA-based multiple molecular dynamics simulation strategy for efficient design and optimization of zinc enzyme inhibitors, reducing computational expense.
Documented Applications
Treatment, prevention, or amelioration of symptoms associated with Botulinum neurotoxin poisoning, including food-borne botulism.
Counteracting Botulinum toxin poisoning arising from cosmetic Botox injections or biological-based weapons.
Use in mammals including humans, cats, dogs, horses, pigs, cows, sheep, mice, rats, and monkeys for Botulinum toxin poisoning treatment.
Interested in licensing this patent?