Abstract: Disclosed are agents that include a flavanol (e.g., epigallocatechin-3-gallate) or a flavanol analog, a linker coupled to the flavanol or the flavanol analog, and a carrier (e.g., iron oxide nanoparticle) coupled to the linker. The disclosed agents can be used in methods for destabilizing a tau amyloid fibril, and for treating a tauopathy (e.g., Alzheimer's disease, progressive supranuclear palsy) in a subject.

Abstract: This invention relates to inhibitory peptides which bind to ?-synuclein molecules and inhibit ?-synuclein amyloidogenic aggregation, ?-synuclein cytotoxicity, and spread of ?-synuclein. Methods of making and using the inhibitory peptides (e.g. to treat subjects having conditions or diseases that are mediated by ?-synuclein, such as Parkinson's disease, dementia with Lewy bodies, or MSA) are described.

Abstract: This invention relates to inhibitory peptides which bind to ?-synuclein molecules and inhibit ?-synuclein amyloidogenic aggregation, ?-synuclein cytotoxicity, and spread of ?-synuclein. Methods of making and using the inhibitory peptides (e.g. to treat subjects having conditions or diseases that are mediated by ?-synuclein, such as Parkinson's disease, dementia with Lewy bodies, or MSA) are described.

Abstract: The invention disclosed herein relates to peptide inhibitors for transthyretin (TTR) aggregation and methods of inhibiting TTR aggregation, cytotoxicity, and/or TTR amyloidosis. Illustrative embodiments of the invention include a composition of matter comprising at least one peptide designed to inhibit the aggregation of TTR, with this peptide typically being coupled to a heterologous amino acid tag. A pharmaceutically acceptable carrier selected to be compatible with the inhibitory peptide may also be included. A method for blocking or inhibiting the aggregation of transthyretin TTR is also provided. The method comprises combining TTR with an effective amount of an inhibitory peptide or pharmaceutical composition, so that TTR aggregation and/or cytotoxicity is blocked or inhibited.

Abstract: Aggregated Tau protein is associated with over 20 neurological disorders including Alzheimer's disease. Previous work has shown that Tau's sequence segments VQIINK (SEQ ID NO: 11) and VQIVYK (SEQ ID NO: 9) drive its aggregation, and that inhibitors based on the structure of the VQIVYK (SEQ ID NO: 9) segment partially inhibit Tau aggregation. Here we show that the VQIINK (SEQ ID NO: 11) segment is the more powerful driver of Tau aggregation. Two structures of this segment determined by the cryo EM method MicroED explain its more powerful seeding. Of practical significance, the understanding of the structures has led to the design of structure based peptide inhibitors that effectively inhibit Tau aggregation as well as the ability of exogenous Tau fibrils to seed intracellular Tau in mammalian cells into amyloid.

Abstract: This invention relates to inhibitory peptides which bind to ?-synuclein molecules and inhibit ?-synuclein amyloidogenic aggregation, ?-synuclein cytotoxicity, and spread of ?-synuclein. Methods of making and using the inhibitory peptides (e.g. to treat subjects having conditions or diseases that are mediated by ?-synuclein, such as Parkinson's disease, dementia with Lewy bodies, or MSA) are described.

Abstract: This invention relates to inhibitory peptides which bind to ?-synuclein molecules and inhibit ?-synuclein amyloidogenic aggregation, ?-synuclein cytotoxicity, and spread of ?-synuclein. Methods of making and using the inhibitory peptides (e.g. to treat subjects having conditions or diseases that are mediated by ?-synuclein, such as Parkinson's disease, dementia with Lewy bodies, or MSA) are described.

Abstract: Aggregated Tau protein is associated with over 20 neurological disorders including Alzheimer's disease. Previous work has shown that Tau's sequence segments VQIINK and VQIVYK drive its aggregation, and that inhibitors based on the structure of the VQIVYK segment partially inhibit Tau aggregation. Here we show that the VQIINK segment is the more powerful driver of Tau aggregation. Two structures of this segment determined by the cryo EM method MicroED explain its more powerful seeding. Of practical significance, the understanding of the structures has led to the design of structure based peptide inhibitors that effectively inhibit Tau aggregation as well as the ability of exogenous Tau fibrils to seed intracellular Tau in mammalian cells into amyloid.

Abstract: The invention disclosed herein relates to peptide inhibitors for transthyretin (TTR) aggregation and methods of inhibiting TTR aggregation, cytotoxicity, and/or TTR amyloidosis. Illustrative embodiments of the invention include a composition of matter comprising at least one peptide designed to inhibit the aggregation of TTR, with this peptide typically being coupled to a heterologous amino acid tag. A pharmaceutically acceptable carrier selected to be compatible with the inhibitory peptide may also be included. A method for blocking or inhibiting the aggregation of transthyretin TTR is also provided.

Abstract: This invention relates, e.g., to an inhibitory peptide or CPP inhibitor which specifically binds to p53 having an aberrant conformation (e.g., is aggregated or misfolded) and inhibits p53 amyloidogenic aggregation or restores proper folding of the misfolded protein. Methods of using the inhibitory peptide or CPP inhibitor (e.g. to treat subjects having tumors that comprise aggregated p53) are described.

Abstract: This invention relates to inhibitory peptides which bind to ?-synuclein molecules and inhibit ?-synuclein amyloidogenic aggregation, ?-synuclein cytotoxicity, and spread of ?-synuclein. Methods of making and using the inhibitory peptides (e.g. to treat subjects having conditions or diseases that are mediated by ?-synuclein, such as Parkinson's disease, dementia with Lewy bodies, or MSA) are described.

Abstract: This invention relates, e.g., to an inhibitory peptide or CPP inhibitor which specifically binds to p53 having an aberrant conformation (e.g., is aggregated or misfolded) and inhibits p53 amyloidogenic aggregation or restores proper folding of the misfolded protein. Methods of using the inhibitory peptide or CPP inhibitor (e.g. to treat subjects having tumors that comprise aggregated p53) are described.

Abstract: This invention relates, e.g., to an inhibitory peptide or CPP inhibitor which specifically binds to p53 having an aberrant conformation (e.g., is aggregated or misfolded) and inhibits p53 amyloidogenic aggregation or restores proper folding of the misfolded protein. Methods of using the inhibitory peptide or CPP inhibitor (e.g. to treat subjects having tumors that comprise aggregated p53) are described.

Abstract: Methods for disrupting amyloid fibrils in a subject, comprising combining an effective amount of a ?-2 microglobulin fibril disrupting compound with a medium associated with the subject, are disclosed. The invention also relates to combining the ?-2 microglobulin fibril disrupting compound ex vivo with the blood during dialysis treatment of an animal. It also relates to methods for determining which compounds are effective at disrupting amyloid fibrils in a medium.

Abstract: This invention relates, e.g., to an inhibitory peptide or CPP inhibitor which specifically binds to p53 having an aberrant conformation (e.g., is aggregated or misfolded) and inhibits p53 amyloidogenic aggregation or restores proper folding of the misfolded protein. Methods of using the inhibitory peptide or CPP inhibitor (e.g. to treat subjects having tumors that comprise aggregated p53) are described.

Abstract: This invention relates, e.g., to a cylindrin, which is a non-covalent assembly of substantially identical chains of an amyloid or amyloid-related protein, which is a non-covalent assembly of substantially identical chains of an amyloid or amyloid-related protein, wherein each chain has a length of about 10-100 amino acid residues and comprises a single copy of a cylindrin-forming segment, or tandem adjacent copies of a cylindrin-forming segment, optionally separated by spacers, or adjacent copies of a first cylindrin-forming segment and a second complementary segment of the first cylindrin-forming segment, optionally separated by spacers, wherein at least about ? of the amino acid residues in the chain are cylindrin-forming segments, wherein the cylindrin is a curved beta sheet formed from anti-parallel out-of-register extended protein strands, which is substantially filled with packed side chains.

Abstract: The invention provides methods for designing peptides that inhibit aggregation in target polypeptides. The candidate inhibitory peptidic compounds have an oligomeric sequence that forms energetically-favorable interactions with the amino acid sequence of the steric zipper region of the target protein, and also possess a zipper-disrupting feature that disrupt the peptide stacking at the steric zipper region. This method can be used to obtain inhibitory peptides to disrupt fibril formation involving any protein for which a steric zipper sequence can be identified. The invention also provides inhibitory peptidic compounds, which can be used in pharmaceutical compositions and methods for treating polypeptide aggregation-associated diseases or conditions.

Abstract: This invention relates, e.g., to a method for designing or selecting on a computer a candidate small molecule amyloid binder or inhibitor, comprising: a) docking test compounds to the binding site or binding surface determined from the three-dimensional structure of a co-crystal of a protofilament of an amyloid protein bound to a small molecule which is known to bind to the amyloid protein, and (b) selecting test compounds which exhibit an energy below that of the small molecule used to form the co-crystal made in a), as candidate amyloid binders.

Abstract: The invention provides methods for designing peptides that inhibit aggregation in target polypeptides. The candidate inhibitory peptidic compounds have an oligomeric sequence that forms energetically-favorable interactions with the amino acid sequence of the steric zipper region of the target protein, and also possess a zipper-disrupting feature that disrupt the peptide stacking at the steric zipper region. This method can be used to obtain inhibitory peptides to disrupt fibril formation involving any protein for which a steric zipper sequence can be identified. The invention also provides inhibitory peptidic compounds, which can be used in pharmaceutical compositions and methods for treating polypeptide aggregation-associated diseases or conditions.

Abstract: Methods for disrupting amyloid fibrils in a subject, comprising combining an effective amount of a ?-2 microglobulin fibril disrupting compound with a medium associated with the subject, are disclosed. The invention also relates to combining the ?-2 microglobulin fibril disrupting compound ex vivo with the blood during dialysis treatment of an animal. It also relates to methods for determining which compounds are effective at disrupting amyloid fibrils in a medium.