Small-molecule botulinum toxin inhibitors
Inventors
Pang, Yuan-Ping • Park, Jewn Giew • Wang, Shaohua • Vummenthala, Anuradha • Mishra, Rajesh K • Davis, Jon • Millard, Charles B. • Schmidt, James J.
Assignees
Mayo Foundation for Medical Education and Research • US Army Medical Research and Development Command
Publication Number
US-8404728-B2
Publication Date
2013-03-26
Expiration Date
2030-07-29
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
This disclosure relates to materials and methods for inhibiting Botulinum neurotoxin, and more particularly to materials and methods for inhibiting the zinc endopeptidase of Botulinum neurotoxin serotypes A, D and/or E (BoNTA, BoNTD and/or BoNTE).
Core Innovation
This disclosure relates to materials and methods for inhibiting Botulinum neurotoxin, particularly targeting the zinc endopeptidase of Botulinum neurotoxin serotypes A, D, and E (BoNTA, BoNTD, BoNTE). The invention provides small-molecule inhibitors capable of inhibiting the zinc protease activity of these neurotoxins, including methods for treating, preventing, or ameliorating symptoms of botulinum poisoning associated with various conditions such as food-borne botulism, infant botulism, wound botulism, adult enteric infectious botulism, inhalation botulism, and poisoning by BoNTA, BoNTD, and BoNTE.
The invention also provides chemical compositions comprising compounds of specific formulas characterized by defined substituents and structural elements designed to interact with the botulinum zinc endopeptidase active site. Methods of administering these compounds, alone or in combination with known therapies such as equine antitoxin or penicillin G, are disclosed. Kits containing these compositions and pharmaceutical formulations including pharmaceutically acceptable carriers are also described.
A computer-assisted molecular modeling approach is incorporated for designing test inhibitors targeting the Botulinum active site based on crystal structure data (PDB code 3BOO). This includes identifying compounds capable of interacting with specific amino acid residues in the active site and evaluating their inhibitory activity. The methodology involves docking simulations, molecular dynamics, and in vitro assays to refine and optimize inhibitor potency.
Claims Coverage
The patent includes one independent claim (#1) directed to a composition comprising a compound of Formula (IIA), as well as claims related to kits and pharmaceutical compositions involving such compounds. The inventive features focus on the structural characteristics and uses of these compounds.
Composition comprising a compound of Formula (IIA)
A composition comprising a compound of Formula (IIA) defined by a specific formula including substituents R1 through R6, and variables X, Y, W, U with precise definitions and ranges for each, having inhibitory activity against Botulinum neurotoxin zinc protease.
Kit including compositions with compounds of Formula (IIA)
A kit comprising the composition with compounds of Formula (IIA), optionally in injectable form, facilitating administration for the treatment or prevention of Botulinum toxin poisoning.
Pharmaceutical composition comprising compounds of Formula (IIA)
A pharmaceutical composition containing the compounds of Formula (IIA) along with pharmaceutically acceptable carriers, excipients, or adjuvants, intended for therapeutic use against Botulinum neurotoxin poisoning.
The claims collectively cover the compositions comprising specific small-molecule inhibitors defined by Formula (IIA), their pharmaceutical formulations, and kits for administration. The inventive features center on the chemical structures of the small-molecule inhibitors and their therapeutic applications for inhibiting Botulinum zinc endopeptidase activity.
Stated Advantages
The compounds exhibit nanomolar affinity and specificity for the zinc protease activity of Botulinum neurotoxin serotype A, D, and E, allowing effective inhibition.
The inhibitors can be used to treat, prevent, or ameliorate one or more symptoms of Botulinum toxin poisoning, including conditions such as food-borne, infant, wound, adult enteric infectious, and inhalation botulism.
The use of computer-assisted molecular modeling enables efficient design, optimization, and refinement of small-molecule Botulinum inhibitors with high specificity and potency.
Pharmaceutical compositions containing these compounds can be formulated for various administration routes including oral, injectable, and topical, facilitating versatile therapeutic applications.
The inhibitors demonstrate improved survival in in vivo mouse models of Botulinum toxin poisoning, indicating practical efficacy.
Documented Applications
Treatment, prevention, or amelioration of symptoms associated with Botulinum toxin poisoning including food-borne botulism, infant botulism, wound botulism, adult enteric infectious botulism, and inhalation botulism.
Use as antidotes to Botulinum neurotoxin serotypes A, D, and E poisoning, including cases of cosmetic BOTOX® overdose or biological weapon exposure.
Combating toxicity from medical toxins based on BoNT/LC-chimeras, such as immunotoxins or pain-receptor-binding proteins linked to BoNTA/LC.
Computer-assisted molecular modeling methods to identify and design small-molecule inhibitors targeting the Botulinum zinc endopeptidase active site for therapeutic applications.
Interested in licensing this patent?