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Publication Number
US-10053677-B2
Publication Date
2018-08-21
Expiration Date
Abstract
A cyclic polypeptide, derivative or analog thereof, comprising an amino acid sequence derived from the C-terminus of acetylcholinesterase (ACh E), or a truncation thereof.
Core Innovation
The invention relates to cyclic polypeptides derived from the C-terminus of tailed acetylcholinesterase (AChE), including cyclic forms of linear peptides T14/T30. It describes cyclic polypeptides such as cyclated T14 (Cyclic T14/CT14/NBP14), produced from a C-terminus derived peptide sequence, and discusses the resulting biological interaction with the nicotinic receptor ( nAChR).
The invention addresses the trophic-to-toxic calcium signaling axis associated with nAChR and an allosteric site, including an ivermectin-sensitive allosteric site. It states that cyclization yields a selective allosteric modulator/antagonist that is inert and non-toxic alone, does not inhibit AChE enzymatic activity, and selectively antagonizes trophic-to-toxic calcium signaling by blocking additional calcium influx through the nAChR allosteric site.
The invention further states that the cyclic polypeptides outcompete linear peptides and b2-amyloid binding, and reduce b2-amyloid-related toxicity. It also states that the cyclic polypeptides block additional calcium influx at the ivermectin-sensitive allosteric site, reduce compensatory AChE release, and reduce intracellular calcium changes, and are discussed for therapeutic/diagnostic uses in neurodegenerative disorders.
Claims Coverage
The claim set includes one independent claim defining a cyclic polypeptide consisting of SEQ ID NO: 4, with dependent claims directed to selective nicotinic receptor allosteric modulation, a pharmaceutical composition, and in vitro or ex vivo analytical investigation of the nAChR allosteric site. The inventive features center on the sequence-defined cyclic polypeptide, inhibition of additional calcium influx and competition with b2-amyloid binding, composition with a pharmaceutically acceptable vehicle, and analytical use.
Cyclic polypeptide consisting of SEQ ID NO: 4.
A cyclic polypeptide consisting of SEQ ID NO: 4.
Selective nicotinic receptor allosteric modulation inhibiting additional calcium influx and outcompeting b2-amyloid binding.
A selective allosteric modulator of the nicotinic-receptor that inhibits additional calcium influx through an allosteric site and outcompetes binding for b2-amyloid.
Receptor allosteric modulator comprising the cyclic polypeptide.
A receptor allosteric modulator comprising the cyclic polypeptide according to claim 1.
Pharmaceutical composition of cyclic polypeptide with a pharmaceutical acceptable vehicle.
A pharmaceutical composition comprising the cyclic polypeptide and a pharmaceutical acceptable vehicle.
Making the pharmaceutical composition by contacting with the vehicle.
A process for making the pharmaceutical composition by contacting the cyclic polypeptide with a pharmaceutically acceptable vehicle.
In vitro or ex vivo analytical method investigating the nicotinic receptor allosteric site by inhibiting additional calcium influx.
A method of using the cyclic polypeptide in an in vitro or ex vivo analytical method for investigating the nicotinic-receptor allosteric site by inhibiting additional calcium influx through the nicotinic receptor.
Overall, the claims center on a cyclic polypeptide consisting of SEQ ID NO: 4, with dependent coverage for selective nicotinic receptor allosteric modulation, pharmaceutical composition, and in vitro or ex vivo analytical use for investigating the nAChR allosteric site.
Stated Advantages
Inert and non-toxic alone.
Does not inhibit AChE enzymatic activity.
Selective antagonism of trophic-to-toxic calcium signaling by blocking additional calcium influx at the nicotinic receptor allosteric site.
Outcompetes linear peptides and b2-amyloid binding.
Reduces b2-amyloid toxicity by blocking additional calcium influx through the ivermectin-sensitive allosteric site.
Reduces compensatory AChE release and reduces intracellular calcium changes.
Documented Applications
Therapeutic and/or diagnostic uses for neurodegenerative disorders, especially Alzheimers disease and Parkinsons disease, including also Motor Neurone disease, Huntingtons disease, Frontotemporal Dementia, ALS, and Spinocerebellar ataxia.
In vitro and ex vivo analytical investigation of the nicotinic receptor allosteric site.
Use in a pharmaceutical composition comprising the cyclic polypeptide and a pharmaceutical acceptable vehicle.
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