COMPUTATIONALLY DESIGNED INHIBITORS OF AMYLOIDOSIS
Embodiments of the present invention include methods and systems for designing inhibitors of amyloidosis in humans, domesticated animals, and wild animals as well as inhibitors of amyloidosis designed by the methods and systems. Methods and systems for designing inhibitors of amyloidosis are largely computational, in nature, and are directed to designing various types of polymers, small-molecule organic compounds, organometallic compounds, or non-chemical physical processes that can target the extended-α-strand and α-sheet regions of amyloidogenic protein and polypeptide intermediates in order to prevent aggregation of those intermediates into protofibrils and fibrils that, in turn, recruit additional native-conformation proteins and polypeptides into amyloidogenic intermediates and that additionally aggregate to form higher-order structures, such as plaques observed in the brains of patients suffering from the various spongiform encephalopathies.
Latest UNIVERSITY OF WASHINGTON Patents:
- METHODS AND COMPOSITIONS FOR GENERATING REFERENCE MAPS FOR NANOPORE-BASED POLYMER ANALYSIS
- HIGH-RESOLUTION SPATIAL TRANSCRIPTOME
- PICOSCALE THIN LAYER CHROMATOGRAPHY FOR ANALYSIS OF SINGLE CELLS AND MICROSAMPLES
- High-throughput single-cell sequencing with reduced amplification bias
- Ensemble-decision aliquot ranking
This invention was made with government support under 5R01-GM050789-13 awarded by the National Institutes of Health. The government has certain rights in the invention.
TECHNICAL FIELDThe present invention is related to the design and development of therapeutics and therapies for treating various amyloid diseases and pathologies, including transmissible spongiform encephalopathies, such as Creutzfeldt-Jakob disease, Huntington's disease and amyotrophic lateral sclerosis, senile systemic amyloidosis, and familial amyloid polyneuropathy and, in particular, to inhibitors of amyloidosis and to a method and system for computationally designing inhibitors of amyloidosis that prevent or ameliorate various amyloid diseases.
BACKGROUND OF THE INVENTIONCurrently, 25 different human amyloid diseases are known. These diseases include Creutzfeldt-Jakob disease, one of a number of transmissible spongiform encephalopathies, Huntington's disease, amyotrophic lateral sclerosis, senile systemic amyloidosis, familial amyloid polyneuropathy, Kennedy disease, and Machado-Joseph Disease. Amyloidosis is characterized by aggregation of proteins and/or peptides, and each different amyloid disease appears to result from partial unfolding and refolding of a particular protein or peptide into an amyloidogenic intermediate, such as the partial unfolding and refolding of the well-known prion protein PrPC into the amyloidogenic intermediate PrPSC, which then aggregates to form larger structures, including fibrils and deposits. Molecular dynamics (“MD”) computational simulations of native-conformation and amyloidogenic-intermediate proteins and peptides have revealed that many of the amyloidogenic-intermediate proteins and peptides exhibit an unusual secondary structure referred to as α-sheet, described in a subsequent section of this document. It has been proposed that regions of α-sheet or extended α-strand within amyloidogenic intermediates provide inter-protein or inter-polypeptide binding sites that allow the soluble amyloidogenic intermediates to aggregate into polymer-like protofibrils and fibrils, which can, in turn, then aggregate into larger, insoluble structures, such as the plaques observed in the brain tissue of patients suffering from various spongiform encephalopathies. The extended-α-strand secondary structure has been only rarely observed in non-amyloidogenic protein structures, and α-sheet secondary structure has not been observed in non-amyloidogenic protein structures, but MD simulations have revealed extended-α-strand and α-sheet secondary structure in those amyloidogenic intermediates so far studied. As discussed below, the extended-α-strand and α-sheet secondary structure features an uncharacteristic dipole moment approximately orthogonal to the polypeptide backbone and features extended chains of carbonyl oxygens, on one side, and amide hydrogens, on the opposite side, both excellent targets for hydrogen bonding. The α-strand and α-sheet secondary structure may be only transiently exhibited during the amyloidosis process, amyloidogenic intermediates, and may transform to β-pleated sheet or other secondary-structure motifs as the conformation of protein and polypeptide monomers within higher-order aggregates, including fibrils and plaques, changes to more stable conformations within the higher-order aggregates.
Human amyloid diseases currently account for annual expenditure of over $100 billion in health care costs, and these costs are rising as more human amyloid diseases are clinically recognized. The costs of caring for those suffering from amyloid diseases may significantly rise with increasing rates of transmission of the transmissible forms of amyloidogenic intermediates, such as the infective prion protein PrPSC. Currently, there are no effective treatments or therapies for amyloid diseases, and the toll in human lives and in the disruptions in lives of family members, care-givers, and employers of those afflicted with amyloid disease is incalculable. Medical and scientific researchers, health care providers, government agencies, and, ultimately, those susceptible to amyloid diseases and those who care for victims of amyloid diseases have all recognized the need for medical therapies for preventing and/or ameliorating amyloid diseases in the human population. The serious impact of amyloid diseases on populations of domesticated and wild animals is also recognized as an enormous problem for which palliative or curative veterinary pharmaceuticals are desperately needed.
SUMMARY OF THE INVENTIONEmbodiments of the present invention include methods and systems for designing inhibitors of amyloidosis in humans, domesticated animals, and wild animals as well as inhibitors of amyloidosis designed by the methods and systems. Methods and systems for designing inhibitors of amyloidosis are largely computational, in nature, and are directed to designing various types of polymers, small-molecule organic compounds, organometallic compounds, or non-chemical physical processes that can target the extended-α-strand and α-sheet regions of amyloidogenic protein and polypeptide intermediates in order to prevent aggregation of those intermediates into protofibrils and fibrils that, in turn, recruit additional native-conformation proteins and polypeptides into amyloidogenic intermediates and that additionally aggregate to form higher-order structures, such as plaques observed in the brains of patients suffering from the various spongiform encephalopathies.
Embodiments of the present invention are directed to computational methods for designing inhibitors of amyloidosis, to small-molecule and polymer amyloidosis inhibitors designed by these computational methods, and even to any of various non-chemical physical processes that may be designed to inhibit computationally derived binding sites at which amyloidogenic intermediates bind together to form polymer-like aggregates. Discussion of the method, system, and therapeutic embodiments of the present invention follows a number of initial subsections, below, that provide overviews of (1) protein and protein structure, including extended α-strand and α-sheet; (2) the process by which certain proteins and polypeptides unfold and refold to produce amyloidogenic precursors and subsequently aggregate to form protofibrils, fibrils, and higher-order structures; and (3) other aspects of amyloid diseases.
Overview of Polypeptides and ProteinsNaturally occurring polypeptides and proteins are, for the most part, polymers of 19 common amino acids and one common imino acid.
In solution, an amino acid may have any of various different ionic forms.
Polypeptides and proteins are generally not linear structures, but are instead folded into elaborate three-dimensional structures that often contain regions of well-defined secondary structure. Two commonly encountered types of secondary structure are α helices and β-pleated sheets. These regular, secondary-structure conformations of polypeptides can be described as a constraining of the Φ and Ψ torsion angles along the polypeptide chain to narrow ranges of values.
Many other different types of structural motifs, characterized by Φ/Ψ constraints, can be found within complex three-dimensional structures of proteins. The three-dimensional structure of proteins is generally quite complex, and determined by many different types of forces and thermodynamic properties, including hydrophobic interactions, solvation, hydrogen bonds, ionic interactions between side chains (R groups). covalent bonds between side chains. The various types of protein functions are partially or fully determined by the three-dimensional structures of proteins, including the shapes, sizes, and arrangement of catalytic groups within catalytic domains of enzymes.
AmyloidosisAmyloidosis is the process by which certain polypeptides and proteins that presumably play various, useful roles in an organism conformationally change to become amyloidogenic intermediates which then aggregate together to form higher-order aggregates. Amyloidosis thus involves only conformational changes, or at least appears to involve only conformational changes in the transformation of the native-conformation protein or polypeptide, referred to below as the “amyloidogenic precursor protein” or “amyloidogenic precursor polypeptide,” to amyloidogenic intermediate. Amyloidogenic-precursor proteins that can generate amyloidogenic intermediates include prion, lysozyme, transthyretin, β-microglobulin and polyglutamine.
For certain amyloidogenic precursor proteins, the equilibrium constant may be so small that no amyloidogenic intermediates would be expected to spontaneously arise, and the conformational transformation of amyloidogenic precursor protein to amyloidogenic intermediate occurs only through conformational recruitment by an amyloidogenic intermediate or amyloidogenic-intermediate containing protofibril of exogenous origin.
Because of the change of conformation from amyloidogenic-precursor protein to amyloidogenic intermediate, binding or docking sites appear, based on MD simulation, to form at or near the exterior surface of the amyloidogenic intermediates. Because of the presence of these binding or docking sites, the amyloidogenic intermediates aggregate together to form protofibrils, an example of which is schematically shown in
In a next step, shown in
As shown in
While the general sequential steps of conformational change and aggregation, illustrated in
Lacking the traditional methods for elucidating structure and conformation of the amyloidogenic intermediates and higher-order aggregates, researchers have applied molecular-dynamics computational simulations (“MD”) in order to model the conformation and structures of the amyloidogenic intermediates and higher-order aggregates. MD simulations may be performed using the program Encad or the program 11 mm. MD simulations start with a molecule in a conformation for which the energy has been minimized and employ mathematical models of force fields about atoms to iteratively compute shifts or adjustments to the conformation that further minimize overall energy of the conformation. Somewhat surprisingly, the MD simulations have consistently shown that extended-α-strand and α-sheet secondary structure may be present in the amyloidogenic intermediates and protofibrils. As discussed in the next subsection, extended α-strand and α-sheet secondary structure in a first amyloidogenic intermediate provides two unusual docking sites for complementary extended α-strand or α-sheet regions in second and third amyloidogenic intermediates, allowing the amyloidogenic intermediates to form oligomeric structures through strong, non-covalent cross-extended-α-strand and cross-a-sheet secondary-structure bonding.
Currently, the cytotoxic effects produced during the course of amyloid diseases are not well understood. While the presence of higher-order aggregates of amyloidogenic-precursor proteins and amyloidogenic-precursor polypeptides within organisms may disrupt normal cell and organ functions, it is currently thought that the amyloidogenic intermediates and initial, smaller aggregates, such as protofibrils, may be responsible for the bulk of the cytotoxic effects observed in amyloid diseases. At least one antibody has been identified that binds to soluble oligomeric amyloidogenic intermediates, but does not bind insoluble fibrils, and does inhibit toxicity. While many believe that the conformational change that produces amyloidogenic intermediates arises either spontaneously, particularly in low pH environments, or may be induced by essentially infective amyloidogenic intermediates or protofibrils, the cause and course of specific pathologies are still not fully explained. However, generation of amyloidogenic intermediates and higher-order aggregates are certain to play a fundamental role in the various types of pathologies. Therefore, therapeutic agents or physical agents that can interrupt the sequence of conformational changes and aggregation illustrated in
Another feature of extended α-strand and α-sheet secondary structure is that the conformation about each successive Cα carbon along each extended α-strand backbone alternates between that typical of a right-handed α helix, or αR, and the conformation typically of a left-handed α helix, αL. In other words, referring to
The zigzag, or pleated, arrangement of carbonyl oxygens that constitutes a first type of binding site in amyloidogenic intermediates, or (−) binding site, and the zigzag, or pleated, arrangement of amide hydrogens that constitutes a second type of binding site in amyloidogenic intermediates, or (+) binding site, complementary to the first type of binding site, or (−) binding site, are, in many ways, ideal targets for amyloidosis inhibitors. These binding sites are uniquely characterized by the above-discussed distance and angle parameters, and the extended-α-strand and α-sheet secondary structure that features these carbonyl-oxygen-rich and amide-hydrogen-rich binding sites are uniquely characterized by the Φ/Ψ torsion angles for alternating αL and αR domains of the polypeptide backbone within extended-α-strand and α-sheet secondary structure. As with any such parametric representation of molecular structure, narrower ranges of angles and distances may be used to characterize extended-α-strand and α-sheet secondary structure and the (+) binding site and (−) binding sites featured by extended-α-strand and α-sheet secondary structure. For example, For example, carbonyl-carbon angles a may be alternatively specified as 148°±20°, 148°±15°, or 148°±10°. The carbonyl-oxygen distances dO-O may be alternatively specified as 3.1±0.3 Å, 3.1±0.2 Å, and 3.1±0.1 Å. The amide-hydrogen angles α may be alternatively specified as 159°±30°, 159°±20°, or 159°±10°. The amide-hydrogen distances may be alternatively specified as 2.9±0.6 Å, 2.9±0.4 Å, or 2.9±0.2 Å. The αR domain Φ/Ψ angles may be alternatively specified as −83.2°±24°/−55.6°±21.9°, −83.2°±15°/−55.6°±15°, or −83.2°±10°/−55.6°±10° and the αL domain Φ/Ψ angles may be alternatively specified as 59.1°±20.7°/−89.9°±30.6°, 59.1°±15°/89.9°±20°, or −59.1°±10°/89.9°±10°.
The amyloidogenic intermediate prion protein PrPSC is shown, by MD simulations, to feature two exposed extended α-strand polypeptide regions, one with carbonyl oxygens facing out from the bulk of the protein and therefore comprising a (−) binding site, and one with amide hydrogens facing out from the bulk of the protein and therefore comprising a (+) binding site. These two binding sites are complementary, and allow each amyloidogenic intermediate protein to bind, through extended α-strand hydrogen bonding, as illustrated in
Taken together, the Φ/Ψ angle-pair constraints, carbonyl-oxygen angles, carbonyl-oxygen distances, amide-hydrogen angles, and amide-hydrogen distances, discussed above with reference to
As discussed in the previous subsection, it appears that amyloidogenic-intermediate aggregation occurs by extensive hydrogen bonding and, perhaps, additional electrostatic and dipole-dipole interactions, between complementary edges of extended-α-strand or α-sheet secondary structure, referred to in this document as (−) and (+) binding sites, respectively, within amyloidogenic intermediates. These carbonyl-oxygen and amide-hydrogen-rich edges are attractive targets for therapeutic agents, for many reasons.
First, extended-α-strand and α-sheet polypeptide secondary structure is rarely observed in non-amyloidogenic proteins and polypeptides. Only 924 structures out of a total of 29,936 structures surveyed in the PDB exhibit extended-α-strand secondary structure, and in the 924 structures, 1,161 occurrences of α-strand are observed. Of the 1,161 occurrences of α-strand, 1093 are three-residue structures, 67 are four-residue structures, and only one has a five-residue stretch. There are no occurrences of α-sheet secondary structure in the surveyed PDB structures. Moreover, in non-amyloidogenic proteins and polypeptides, the observed extended-α-strand secondary structure may not occur as complementary (−) and (+) binding sites extending from the surface of the protein or polypeptide. Therefore, therapeutic agents that specifically target the edges of extended α-strand and α-sheet secondary structure most likely target only amyloidogenic intermediates, and do not inadvertently bind to non-target molecules with concomitant potential side effects.
Second, the carbonyl-oxygen-rich and amide-hydrogen-rich edges of extended α-strand and α-sheet secondary structure provide targets for very strong, specific binding by complementary therapeutic agents and, therefore, when the therapeutic agents can be delivered to sites of amyloidosis within organisms at even relatively small concentrations, there is a strong likelihood that they will strongly or irreversibly bind to the docking sites on amyloidogenic intermediates and inhibit or prevent the chain of events leading from amyloidogenic intermediates to protofibrils, fibrils, and higher-order structure. When the therapeutic agents can be designed to elicit protein-destruction pathways within cells and organisms, or elicit an immune response once bound to the complementary docking sites on amyloidogenic intermediates, the amyloidogenic intermediates complexed with therapeutic molecules may be cleared from cells and organisms, completely halting the chain of events leading to amyloidosis.
Third, judging from the ability of extremely small quantities of exogenous infectious amyloidogenic intermediates to enter animals through the circulatory systems and digestive systems of the organisms and find their way to target locations within the brains of the animals, delivery of chemically similar therapeutic agents to therapeutic targets may be expected to not present a difficult problem. This property of infectious amyloidogenic intermediates may be related to the lack of non-target complementary binding sites in normal cells and organisms as well as an extremely high specificity for particular target amyloidogenic-precursor proteins.
Many different possible therapeutic agents may be designed to target extended α-strand or α-sheet binding sites in amyloidogenic intermediates. It is possible that small-molecule or organometallic compounds that recognize the zigzag-like arrangement of carbonyl oxygens or amide hydrogens may be developed to tightly bind to the amyloidogenic-intermediate binding sites and thus prevent aggregation. Synthetic polypeptides and peptidomimetic compounds may be designed to exhibit extended-α-strand or α-sheet secondary structure and thus provide complementary edges for binding to the binding sites of amyloidogenic intermediates. Other biopolymers, including nucleic-acid biopolymers, glycoproteins, and even polysaccharides may be designed to recognize and bind to exposed α-strand or α-sheet edges. Various types of biopolymers and small-molecule therapeutic agents can be designed by computational drug-design methods to target the well-characterized extended α-strand or α-sheet carbonyl-oxygen and amide-hydrogen-rich edges.
One Therapeutic-Agent Embodiment of the Present InventionAlthough the present invention has been described in terms of particular embodiments, it is not intended that the invention be limited to these embodiments. Modifications within the spirit of the invention will be apparent to those skilled in the art. For example, as discussed above, any of a variety of different types of biopolymers, small-molecule compounds, and other compounds can be computationally designed to recognize and bind to the carbonyl-oxygen-rich and/or amide-hydrogen-rich edge regions of extended-α-strand and α-sheet secondary structure within amyloidogenic intermediates. Synthetic peptides, peptidomimetic compounds, RNA, and other types of biopolymers may be designed to provide a complementary binding region, with complementarity mediated by weakly acidic or weakly basic substituent groups that are arranged in a proper geometry to form hydrogen bonds with extended α-strand edges, or by substituent groups having complementary localized dipole moments and complementary overall dipole moments to bind electrostatically to the extended α-strand binding sites of amyloidogenic intermediates. In addition, therapeutic inhibitors may be supplemented with additional, chemically reactive groups that can transfer chemical groups to the amyloidogenic intermediates, covalently bond to the amyloidogenic intermediates, and catalytically cleave amyloidogenic intermediates. Molecular-dynamics-based computational therapeutic-design methods can be programmed in numerous different programming languages for execution on a variety of different hardware and software platforms, and many different alternative implementations can be obtained by changing the well-known and familiar programming parameters, including modular organization, control structures, data structures, and variables, and by use of different pre-existing library routines and programs. Because the extended-α-strand or α-sheet secondary structure appears to be a common motif in all of the currently known amyloidogenic intermediates, it is reasonable to expect that therapeutic small-molecule compounds may have benefit in treating and preventing a variety of different amyloid diseases.
The foregoing description, for purposes of explanation, used specific nomenclature to provide a thorough understanding of the invention. However, it will be apparent to one skilled in the art that the specific details are not required in order to practice the invention. The foregoing descriptions of specific embodiments of the present invention are presented for purpose of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in view of the above teachings. The embodiments are shown and described in order to best explain the principles of the invention and its practical applications, to thereby enable others skilled in the art to best utilize the invention and various embodiments with various modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the following claims and their equivalents:
Claims
1-5. (canceled)
6. An isolated chemical compound designed to bind to an exposed edge of extended-α-strand binding site(s) of an amyloidogenic intermediate through a series of polypeptide-backbone carbonyl-oxygen atoms and/or corresponding polypeptide backbone amide hydrogen atoms, the chemical compound comprising
- (i) at least 3 hydrogen atoms arranged to complement at least 3 carbonyl-oxygen atoms exposed on the oxygen face of an edge of an extended-α-strand binding site of an amyloidogenic intermediate by hydrogen bonding; at least 3 weakly-basic groups to which the hydrogen atoms are covalently bound; and a carbon-based organic-compound structure to which the weakly-basic groups are covalently bound and which provides a conformationally stable platform that arranges the weakly-basic groups and the hydrogen atoms bound to the weakly-basic groups in a linear arrangement complementary to the extended-α-strand binding site of an amyloidogenic intermediate and/or
- (ii) at least 3 atoms with one or more lone-pair electrons arranged to complement at least 3 amide-hydrogen atoms exposed on the hydrogen face of an edge of an extended-α-strand binding site of an amyloidogenic intermediate by hydrogen bonding; and a carbon-based organic-compound structure to which the atoms with one or more lone-pair electrons are covalently bound and which provides a conformationally stable platform that arranges the atoms with one or more lone-pair electrons in a linear arrangement complementary to the extended-α-strand binding site of an amyloidogenic intermediate.
7-23. (canceled)
24. The isolated chemical compound of claim 6, wherein the compound comprises both (i) and (ii).
25. The isolated chemical compound of claim 6 wherein the chemical compound is a polypeptide, and wherein the arrangement complementary to the extended-α-strand binding site of an amyloidogenic intermediate comprises a sequence of amino-acid monomers characterized by:
- alternating αL and αR domains, each domain comprising a single amino-acid monomer;
- Φ angles of 59°±21° about the Cα carbon in the αL domain;
- Ψ angles of 90°±31° about the Cα carbon in the αL domain;
- Φ angles of −83°±25° about the Cα carbon in the αR domain; and
- Ψ angles of −56°±23° about the Cα carbon in the αR domain.
26. The isolated chemical compound of claim 24 wherein the chemical compound is a polypeptide, and wherein the arrangement complementary to the extended-α-strand binding site of an amyloidogenic intermediate comprises a sequence of amino-acid monomers characterized by:
- alternating αL and αR domains, each domain comprising a single amino-acid monomer;
- Φ angles of 59°±21° about the Cα carbon in the αL domain;
- Ψ angles of 90°±31° about the Cα carbon in the αL domain;
- Φ angles of −83°±25° about the Cα carbon in the αR domain; and
- Ψ angles of −56°±23° about the Cα carbon in the αR domain.
27. The isolated chemical compound of claim 25 wherein the chemical compound comprises at least 3 atoms with lone pair electrons arranged to complement the amide hydrogen atoms exposed on the hydrogen face at the edge of the extended-α-strand binding site of the amyloidogenic intermediate by hydrogen bonding, wherein the at least 3 lone-pair atoms are carbonyl oxygen atoms positioned in a linear arrangement with acute angles between successive triples of carbonyl oxygen atoms of 148°±26°, a distance between successive carbonyl-oxygen atoms dO-O of 3.1.±.0.4 Å, and a distance between every other carbonyl-oxygen atom dO-O-O of 5.95±0.8 Å.
28. The isolated chemical compound of claim 26 wherein the chemical compound comprises at least 3 atoms with lone pair electrons arranged to complement the amide hydrogen atoms exposed on the hydrogen face at the edge of the extended-α-strand binding site of the amyloidogenic intermediate by hydrogen bonding, wherein the at least 3 lone-pair atoms are carbonyl oxygen atoms positioned in a linear arrangement with acute angles between successive triples of carbonyl oxygen atoms of 148°±26°, a distance between successive carbonyl-oxygen atoms dO-O of 3.1.±.0.4 Å, and a distance between every other carbonyl-oxygen atom dO-O-O of 5.95±0.8 Å.
29. The isolated chemical compound of claim 25 wherein the chemical compound comprises a series of hydrogen atoms to complement the carbonyl oxygen atoms exposed on the oxygen face at the edge of the extended α-strand binding site of the amyloidogenic intermediate by hydrogen bonding, wherein the hydrogen atoms are positioned in a linear arrangement with acute angles between successive triples of hydrogen atoms of 159°±30°, a distance between successive hydrogen atoms dH-H of 2.9±0.8 Å, and a distance between every other hydrogen atom dH-H-H of 5.6±1.6 Å.
30. The isolated chemical compound of claim 26 wherein the chemical compound comprises a series of hydrogen atoms to complement the carbonyl oxygen atoms exposed on the oxygen face at the edge of the extended α-strand binding site of the amyloidogenic intermediate by hydrogen bonding, wherein the hydrogen atoms are positioned in a linear arrangement with acute angles between successive triples of hydrogen atoms of 159°±30°, a distance between successive hydrogen atoms dH-H of 2.9±0.8 Å, and a distance between every other hydrogen atom dH-H-H of 5.6±1.6 Å.
31. The isolated chemical compound of claim 27 wherein the chemical compound comprises a series of hydrogen atoms to complement the carbonyl oxygen atoms exposed on the oxygen face at the edge of the extended α-strand binding site of the amyloidogenic intermediate by hydrogen bonding, wherein the hydrogen atoms are positioned in a linear arrangement with acute angles between successive triples of hydrogen atoms of 159°±30°, a distance between successive hydrogen atoms dH-H of 2.9±0.8 Å, and a distance between every other hydrogen atom dH-H-H of 5.6±1.6 Å.
32. The isolated chemical compound of claim 28 wherein the chemical compound comprises a series of hydrogen atoms to complement the carbonyl oxygen atoms exposed on the oxygen face at the edge of the extended α-strand binding site of the amyloidogenic intermediate by hydrogen bonding, wherein the hydrogen atoms are positioned in a linear arrangement with acute angles between successive triples of hydrogen atoms of 159°±30°, a distance between successive hydrogen atoms dH-H of 2.9±0.8 Å, and a distance between every other hydrogen atom dH-H-H of 5.6±1.6 Å.
33. The isolated chemical compound of claim 6, wherein the compound comprises
- (i) at least 4 hydrogen atoms arranged to complement at least 4 carbonyl-oxygen atoms exposed on the oxygen face of the edge of an extended-α-strand binding site of the amyloidogenic intermediate by hydrogen bonding; and/or
- (ii) at least 4 atoms with one or more lone-pair electrons arranged to complement at least 4 amide hydrogens exposed at the edge of an extended-α-strand binding site of an amyloidogenic intermediate by hydrogen bonding.
34. The isolated chemical compound of claim 24, wherein the compound comprises
- (i) at least 4 hydrogen atoms arranged to complement at least 4 carbonyl-oxygen atoms exposed on the oxygen face of the edge of an extended-α-strand binding site of the amyloidogenic intermediate by hydrogen bonding; and
- (ii) at least 4 atoms with one or more lone-pair electrons arranged to complement the at least 4 amide hydrogen atoms exposed at the edge of an extended-α-strand binding site of an amyloidogenic intermediate by hydrogen bonding.
35. The isolated chemical compound of claim 6, wherein the compound comprises
- (i) at least 5 hydrogen atoms arranged to complement the at least 5 carbonyl-oxygen atoms exposed on the oxygen face of the edge of an extended-α-strand binding site of the amyloidogenic intermediate by hydrogen bonding; and/or
- (ii) at least 5 atoms with one or more lone-pair electrons arranged to complement the at least 5 amide hydrogen atoms exposed at the edge of an extended-α-strand binding site of an amyloidogenic intermediate by hydrogen bonding.
36. The isolated chemical compound of claim 24, wherein the compound comprises
- (i) at least 5 hydrogen atoms arranged to complement at least 5 carbonyl-oxygen atoms exposed on the oxygen face of the edge of an extended-α-strand binding site of the amyloidogenic intermediate by hydrogen bonding; and
- (ii) at least 5 atoms with one or more lone-pair electrons arranged to complement the at least 5 amide hydrogens atoms exposed at the edge of an extended-α-strand binding site of an amyloidogenic intermediate by hydrogen bonding.
37. The isolated chemical compound of claim 6 wherein the chemical compound is selected from the group consisting of an organic compound; an organometallic compound; a polypeptide; a peptidomimetic compound; an RNA; and a modified RNA.
38. The isolated chemical compound of claim 24 wherein the chemical compound is selected from the group consisting of an organic compound; an organometallic compound; a polypeptide; a peptidomimetic compound; an RNA; and a modified RNA.
Type: Application
Filed: Jul 17, 2012
Publication Date: Nov 8, 2012
Applicant: UNIVERSITY OF WASHINGTON (SEATTLE, WA)
Inventors: Valerie Daggett (Woodinville, WA), Peter Law (Seattle, WA)
Application Number: 13/550,727
International Classification: C07K 14/00 (20060101);