Molecular tweezers for the treatment of amyloid-related diseases
Inventors
Bitan, Gal • Shanmugam, Akila • Lomakin, Aleksey • Schrader, Thomas • Klarner, Frank Gerrit • Talbiersky, Peter • Polkowska, Jolanta • Bastkowski, Frank • Sinha, Sharmistha • Frautschy, Sally
Assignees
Universitaet Duisburg Essen • Massachusetts Institute of Technology • US Department of Veterans Affairs • University of California San Diego UCSD
Publication Number
US-8791092-B2
Publication Date
2014-07-29
Expiration Date
2030-03-05
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Abstract
This invention provides novel compositions to inhibit the aggregation of amyloid proteins. In various embodiments the compositions comprise a molecular tweezers that binds lysine and/or arginine and thereby inhibits the aggregation of amyloidogenic proteins.
Core Innovation
This invention provides compositions comprising molecular tweezers that bind lysine and/or arginine residues to inhibit the aggregation of amyloidogenic proteins. These molecular tweezers are described by formulas I-IV and have been demonstrated to prevent the misfolding and aggregation processes associated with amyloidosis, a pathogenic process leading to insoluble amyloid fibers characterized by β-sheet structures.
Amyloidosis underlies a range of diseases, including Alzheimer's disease (AD), which currently lacks a cure or preventive treatments. Existing therapies address only symptoms and offer moderate, temporary relief. Given that amyloidogenic proteins misfold, oligomerize, and aggregate via a common pathway involving β-sheet formation, inhibiting this aggregation represents a key therapeutic target. Previous inhibitors have lacked a well-understood mechanism, whereas this invention offers molecular tweezers with defined binding properties designed to inhibit amyloid protein assembly.
The molecular tweezers were found to bind specifically to lysine and arginine residues within amyloidogenic proteins, thus inhibiting their aggregation and toxicity. Experimental evidence shows that the molecular tweezers inhibit amyloid beta (Aβ) aggregation, disaggregate pre-formed fibrils, and reduce cytotoxicity both in vitro and in vivo. The invention also provides pharmaceutical formulations of these tweezers for various routes of administration, making them suitable candidates for treatment of amyloid-related disorders.
Claims Coverage
The patent includes multiple independent claims relating to molecular tweezers compositions and pharmaceutical formulations. The following inventive features capture the main aspects of these claims.
Molecular tweezers composition with specific chemical formulas
The invention claims molecular tweezers having one of the formulas I-IV, which include defined substituents (C1-C4) and functional groups (A and B) such as phosphate, phosphonate, phosphamide, sulfate, or carboxylate. Variations include the specific identity of these substituents and their combinations, with the possibility of the tweezers being attached to a second molecular tweezers.
Pharmaceutical formulation comprising molecular tweezers
The invention claims pharmaceutical formulations that comprise the molecular tweezers of any of the formulas I-IV together with a pharmaceutically acceptable excipient. The formulations may be designed for various administration routes including intraperitoneal, topical, oral, inhalation, transdermal, subdermal depot, sub-dural, and rectal administration, and can be prepared as unit dosage forms.
The independent claims cover molecular tweezers compositions defined by specific chemical formulas and their pharmaceutical formulations suitable for diverse administration methods. These claims protect both the molecular tweezers themselves and their use in therapeutic compositions aimed at inhibiting amyloid protein aggregation.
Stated Advantages
Inhibition of aggregation and toxicity of amyloidogenic proteins, including Aβ, which is implicated in Alzheimer's disease and related amyloidoses.
Capability to disaggregate pre-formed amyloid fibrils, reversing amyloid aggregation.
Molecular tweezers (specifically TW1) demonstrated non-toxicity and protective effects in cell culture and animal models.
Potential for improved cognitive function shown in transgenic mouse models of Alzheimer's disease.
Broad applicability to various amyloidogenic proteins, suggesting a general platform for treatment of multiple amyloid-related diseases.
Documented Applications
Use of molecular tweezers to inhibit aggregation of amyloidogenic proteins such as Aβ40, Aβ42, calcitonin, β2-microglobulin, insulin, islet amyloid polypeptide (IAPP), and prion protein fragment 106-126.
Treatment and prevention of disorders associated with amyloidosis, including Alzheimer's disease, cerebral amyloid angiopathy, type 2 diabetes mellitus, medullary carcinoma of the thyroid, and dialysis-related amyloidosis, among others listed in Table 1.
Pharmaceutical compositions of molecular tweezers for administration via routes including oral, intraperitoneal, topical, inhalation, transdermal, subdermal depot, sub-dural, and rectal to patients with amyloid-related diseases.
Use of molecular tweezers as pharmacological agents to mitigate symptoms, slow progression, or improve quality of life for subjects diagnosed with or at risk for amyloidotic diseases.
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