Computationally designed inhibitors of amyloidosis

Abstract

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.

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 C α  carbon in the α L  domain; 
 Ψ angles of 90°±31° about the C α  carbon in the α L  domain; 
 Φ angles of −83°±25° about the C α  carbon in the α R  domain; and 
 Ψ angles of −56°±23° about the C α  carbon in the α R  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 C α  carbon in the α L  domain; 
 Ψ angles of 90°±31° about the C α  carbon in the α L  domain; 
 Φ angles of −83°±25° about the C α  carbon in the α R  domain; and 
 Ψ angles of −56°±23° about the C α  carbon in the α R  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 d O-O  of 3.1.±.0.4 Å, and a distance between every other carbonyl-oxygen atom d O-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 d O-O  of 3.1.±.0.4 Å, and a distance between every other carbonyl-oxygen atom d O-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 d H-H  of 2.9±0.8 Å, and a distance between every other hydrogen atom d H-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 d H-H  of 2.9±0.8 Å, and a distance between every other hydrogen atom d H-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 d H-H  of 2.9±0.8 Å, and a distance between every other hydrogen atom d H-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 d H-H  of 2.9±0.8 Å, and a distance between every other hydrogen atom d H-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.