Self-assembling amphiphilic peptides
Inventors
Assignees
US Department of Agriculture USDA
Publication Number
US-10570172-B1
Publication Date
2020-02-25
Expiration Date
2029-09-30
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Abstract
Self assembling peptides in combination with infectious and non-infectious proteins as inhibitors and diagnostic tools in transmissible spongiform encephalopathies and amyloid producing neuorodegenerative diseases are described herein.
Core Innovation
The invention relates to self-assembling amphiphilic peptides that form stable beta-sheet structures and are used in combination with infectious and non-infectious amyloid or prion proteins. These compositions act as inhibitors and diagnostic tools in transmissible spongiform encephalopathies (TSEs) and other amyloid-producing neurodegenerative diseases. A preferred self-assembling peptide is RADA-16, which forms hydrated beta-sheet nanofiber scaffolds that promote cell attachment and differentiation. The peptides can be modified by amino acid substitutions, such as D-amino acids, to enhance stability and structural switching under varying conditions.
The problem being solved is the current lack of effective clinical treatments for prion diseases, which are incurable and fatal neurodegenerative disorders characterized by abnormal prion protein accumulation, neuronal death, and brain tissue vacuolation. Existing chemical agents fail to provide significant therapeutic benefit, and only genetic ablation of PrPc has shown prevention in animal models. The molecular conversion of normal prion protein (PrPc) to the infectious isoform (PrPsc) is not well understood, and few interventions have delayed disease onset. The invention proposes amphiphilic peptides that disrupt amyloid polymerization, promote amyloid clearance, and potentially elicit beneficial immune responses to facilitate degradation of aggregates.
The compositions comprise charged amphiphilic peptides that self-assemble into beta-sheet rich filaments and bind to amyloid proteins. These peptides, when combined with non-infectious prion or amyloid peptides, form complexes that associate with endogenous amyloids to inhibit further polymerization, promote depolymerization, and serve as novel substrates to elicit immune degradation. The methods include treating neurodegenerative diseases by administering these amphiphilic peptide compositions to target and destabilize amyloid deposits and induce immunomodulatory responses that facilitate clearance of pathological aggregates.
Claims Coverage
The patent contains four main claims, including one composition claim and three method and formulation claims relating to self-assembling peptides, compositions, and treatment methods for amyloid-related diseases.
Composition comprising RADA-16 self-assembling amphiphilic peptide binding amyloid
The invention includes a composition that comprises an amphiphilic peptide capable of self-assembling into a stable beta-sheet structure that binds amyloid, combined with a non-infectious amyloid or prion peptide and a pharmaceutically acceptable carrier. The peptide specifically identified is RADA-16.
Inclusion of metal ions conferring complementary beta sheet structure
The composition further includes metal ions, such as Cu2+ ions, that confer a complementary beta-sheet structure to enhance binding properties or stability.
Method of treating protein misfolding diseases using the composition
A method is disclosed for treating diseases arising from the accumulation of abnormal amyloid aggregates or protein misfolding by administering the composition containing the self-assembling peptide RADA-16 and non-infectious amyloid or prion peptides. Diseases specifically listed include Scrapie, Chronic Wasting Disease, BSE, CJD, vCJD, GSS, FSE, and Exotic ungulate encephalopathy prions.
The claims focus on the composition featuring RADA-16 amphiphilic peptides combined with non-infectious amyloid or prion peptides optionally including metal ions, and methods of treatment of neurodegenerative diseases caused by amyloid aggregation and prion misfolding using these compositions.
Stated Advantages
Compositions are composed of normal biological constituents, biodegradable, free of animal contaminants, and do not provoke immune or inflammatory responses.
The amphiphilic peptides disrupt endogenous amyloid polymerization and promote degradation and clearance of existing amyloid deposits.
The complexes formed target and alter prion distribution, delaying clinical symptoms and extending survival in animal models.
The compositions serve as novel immunogens for generating antibodies specifically against infectious prion isoforms.
The peptides can be used as diagnostic probes for imaging amyloid deposits in brain and other organs.
The use of chiral amino acid modifications enhances peptide stability and enables reversible secondary structure switching.
Documented Applications
Therapeutic agents for treatment and prevention of transmissible spongiform encephalopathies and other amyloid-related neurodegenerative diseases by targeting amyloid deposits to disrupt aggregation and promote clearance.
Diagnostic kits for capture, enrichment, and detection of infectious prions or amyloid proteins from biological samples.
Depletion of infectious prions and aggregate amyloid proteins from biological samples such as blood.
In vivo amyloid imaging probes for diagnostic imaging of cerebral prion or amyloid deposits.
Generation of antibodies specific for the infectious prion isoform by immunization with amphiphilic peptide-prion amyloid complexes.
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