US2003158096A1PendingUtilityA1

Novel molecule

38
Priority: Oct 13, 1999Filed: Apr 12, 2002Published: Aug 21, 2003
Est. expiryOct 13, 2019(expired)· nominal 20-yr term from priority
Inventors:David James CraikNorello DalyClements Waine
A61P 7/00A61P 25/00A61P 17/00A61P 15/00C07K 14/811C07K 14/001C07K 14/415C07K 14/472C07K 14/723
38
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Claims

Abstract

The present invention relates generally to a molecular framework having a cyclic structure. More particularly, the present invention provides cyclic proteins and derivatives thereof in which particular turns and other elements of the molecular structure are held in defined orientations with respect to each other. The cyclic proteins of the present invention provide a molecular framework for the introduction of particular amino acids or heterologous amino acid sequences to facilitate the presentation of biological activities associated with these heterologous amino acid sequences. The molecular framework of the present invention may be naturally cyclic or may be a cyclized derivative of a linear molecular or may be a linear derivative of a cyclized molecule. The present invention contemplates the use of the molecular framework with or without particular amino acids inserted or substituted thereon for the treatment of or prophylaxis of disease conditions in animals, mammals (including humans) and plants.

Claims

exact text as granted — not AI-modified
1 . An isolated molecule which acts as a molecular framework for exogenous amino acids or amino acid sequences, said molecule comprising a sequence of amino acids or analogues thereof forming a cyclic backbone wherein the cyclic backbone comprises sufficient disulfide bonds or chemical equivalents thereof to confer knotted topology on the three-dimensional structure and having the following structure:— 
       
         
           
           
               
               
           
         
       
       wherein 
 C is cysteine;  
 each of [X 1  . . . X a ], [X I   1  . . . X I   b ], [X II   1  . . . X II   c ], [X III   1  . . . X III   d ], [X IV   1  . . . X IV   e ] and [X V   1  . . . X V   f ] represents one or more amino acid residues wherein each one or more amino acid residues within or between the sequence residues may be the same or different; and  
 wherein a, b, c, d, e and f represent the number of amino acid residues in each respective sequence and each of a to f may be the same or different and range from 1 to about 20;  
 or an analogue of said sequence.  
 
     
     
         2 . An isolated molecule according to  claim 1  wherein the each of a to f ranges from about 1 to about 10.  
     
     
         3 . An isolated molecule according to  claim 1  or  2  wherein a, b, c, d, e and f represent the number of amino acid residues in each respective sequence and wherein a is from about 3 to about 6, b is from about 3 to about 5, c is from about 2 to about 7, d is about 1 to about 3, e is about 3 to about 6 and f is from about 4 to about 9.  
     
     
         4 . An isolated molecule according to  claim 1  or  2  wherein a, b, c, d, e and f represent the number of amino acid residues in each respective sequence and wherein a is about 3, b is about 4, c is from about 4 to about 7, d is about 1, e is about 4 or 5 and f is from about 4 to about 7.  
     
     
         5 . An isolated molecule according to  claim 1  or  2  wherein a, b, c, d, e and f represent the number of amino acid residues in each respective sequence and wherein a is about 6, b is about 5, c is about 3, d is about 1, e is about 5 and f is about 8.  
     
     
         6 . An isolated molecule according to  claim 1  wherein the cyclic backbone comprises at least two disulfide bonds.  
     
     
         7 . An isolated molecule according to  claim 6  wherein the cyclic backbone comprises a cystine knot.  
     
     
         8 . An isolated molecule according to  claim 7  wherein the cystine knot comprises at least three disulfide bonds.  
     
     
         9 . An isolated molecule according to  claim 7  wherein the cystine knot comprises more than three disulfide bonds.  
     
     
         10 . An isolated molecule according to  claim 1  comprising the sequence set forth in <400>1.  
     
     
         11 . An isolated molecule according to  claim 1  comprising the sequence set forth in <400>2.  
     
     
         12 . An isolated molecule according to  claim 1  comprising the sequence set forth in <400>3.  
     
     
         13 . An isolated molecule according to  claim 1  comprising the sequence set forth in <400>4.  
     
     
         14 . An isolated molecule according to  claim 1  comprising the sequence set forth in <400>5.  
     
     
         15 . An isolated molecule according to  claim 1  comprising the sequence set forth in <400>6.  
     
     
         16 . An isolated molecule according to  claim 1  comprising the sequence set forth in <400>7.  
     
     
         17 . An isolated molecule according to  claim 1  comprising the sequence set forth in <400>8.  
     
     
         18 . An isolated molecule according to  claim 1  comprising the sequence set forth in <400>9.  
     
     
         19 . An isolated molecule according to  claim 1  comprising the sequence set forth in <400>10.  
     
     
         20 . An isolated molecule according to  claim 1  comprising the sequence set forth in <400>11.  
     
     
         21 . An isolated molecule according to  claim 1  comprising the sequence set forth in <400>12.  
     
     
         22 . An isolated molecule according to  claim 1  comprising the sequence set forth in <400>13.  
     
     
         23 . An isolated molecule according to  claim 1  comprising the sequence set forth in <400>19.  
     
     
         24 . An isolated molecule according to  claim 1  comprising the sequence set forth in <400>20.  
     
     
         25 . An isolated molecule according to  claim 1  comprising the sequence set forth in <400>21.  
     
     
         26 . An isolated molecule which acts as a molecular framework for exogenous amino acids or amino acid sequences, said molecule comprising a sequence of amino acids or analogues thereof forming a cyclic backbone and wherein said cyclic backbone comprises sufficient disulfide bonds or chemical equivalents thereof, to confer a knotted topology on the three-dimensional structure of said cyclic backbone and wherein at least one exposed amino acid residue on a beta turn and/or other part of the backbone is inserted or substituted or otherwise grafted relative to the naturally occurring amino acid sequence.  
     
     
         27 . An isolated molecule according to  claim 26  wherein the other part of the backbone is one or more loops.  
     
     
         28 . An isolated molecule according to  claim 26  or  27  wherein two or more amino acid sequences are inserted, substituted or otherwise grafted onto the backbone.  
     
     
         29 . An isolated molecule according to  claim 26  wherein the cyclic bone comprises at least two disulfide bonds.  
     
     
         30 . An isolated molecule according to  claim 29  wherein the cyclic backbone comprises a cystine knot or its chemical or structural equivalent.  
     
     
         31 . An isolated molecule according to  claim 30  wherein the cystine knot comprises at least three disulfide bonds.  
     
     
         32 . An isolated molecule according to  claim 30  wherein the cystine knot comprises more than three disulfide bonds.  
     
     
         33 . An isolated molecule according to any one of  claims 26  to  32  wherein the inserted or substituted or otherwise grafted amino acid residues are a single residue or a linear sequence of from about 2 residues to about 60 residues.  
     
     
         34 . An isolated molecule according to  claim 33  wherein the inserted or substituted or otherwise grafted amino acid residues are a single residue or a linear sequence of from about 2 residues to about 30 residues.  
     
     
         35 . An isolated molecule according to any one of  claims 26  to  34  wherein the inserted or substituted or otherwise grafted amino acid residues are a single residue or a linear sequence of from about 2 residues to about 10 residues.  
     
     
         36 . An isolated molecule according to  claim 35  comprising the amino acid sequence set forth in <400>38.  
     
     
         37 . An isolated molecule according to  claim 35  comprising the amino acid sequence set forth in <400>39.  
     
     
         38 . An isolated molecule according to  claim 35  comprising the amino acid sequence set forth in <400>40.  
     
     
         39 . An isolated molecule according to  claim 35  comprising the amino acid sequence set forth in <400>41.  
     
     
         40 . An isolated molecule according to  claim 35  comprising the amino acid sequence set forth in <400>42.  
     
     
         41 . An isolated molecule according to  claim 35  comprising the amino acid sequence set forth in <400>43.  
     
     
         42 . An isolated molecule according to  claim 35  comprising the amino acid sequence set forth in <400>44.  
     
     
         43 . An isolated molecule according to  claim 35  comprising the amino acid sequence set forth in <400>45.  
     
     
         44 . An isolated molecule according to any one of  claims 26  to  35  wherein the molecular framework is a modulator of calcium channel-binding ability, C5a binding activity, proteinase inhibitor activity in plants or animals, antibiotic activity, HIV, plant pathogen activity, microbial activity, fungal activity, viral activity, cytokine binding ability and blood clot inhibiting ability.  
     
     
         45 . An isolated molecule according to  claim 26  wherein the cyclic backbone comprises the sequence set forth in <400>1.  
     
     
         46 . An isolated molecule according to  claim 26  wherein the cyclic backbone comprises the sequence set forth in <400>2.  
     
     
         47 . An isolated molecule according to  claim 26  wherein the cyclic backbone comprises the sequence set forth in <400>3.  
     
     
         48 . An isolated molecule according to  claim 26  wherein the cyclic backbone comprises the sequence set forth in <400>4.  
     
     
         49 . An isolated molecule according to  claim 26  wherein the cyclic backbone comprises the sequence set forth in <400>5.  
     
     
         50 . An isolated molecule according to  claim 26  wherein the cyclic backbone comprises the sequence set forth in <400>6.  
     
     
         51 . An isolated molecule according to  claim 26  wherein the cyclic backbone comprises the sequence set forth in <400>7.  
     
     
         52 . An isolated molecule according to  claim 26  wherein the cyclic backbone comprises the sequence set forth in <400>8.  
     
     
         53 . An isolated molecule according to  claim 26  wherein the cyclic backbone comprises the sequence set forth in <400>9.  
     
     
         54 . An isolated molecule according to  claim 26  wherein the cyclic backbone comprises the sequence set forth in <400>10.  
     
     
         55 . An isolated molecule according to  claim 26  wherein the cyclic backbone comprises the sequence set forth in <400>11.  
     
     
         56 . An isolated molecule according to  claim 26  wherein the cyclic backbone comprises the sequence set forth in <400>12.  
     
     
         57 . An isolated molecule according to  claim 26  wherein the cyclic backbone comprises the sequence set forth in <400>13.  
     
     
         58 . An isolated molecule according to  claim 26  wherein the cyclic backbone comprises the sequence set forth in <400>19.  
     
     
         59 . An isolated molecule according to  claim 26  wherein the cyclic backbone comprises the sequence set forth in <400>20.  
     
     
         60 . An isolated molecule according to  claim 26  wherein the cyclic backbone comprises the sequence set forth in <400>21.  
     
     
         61 . A precursor of a molecule defined in  claim 1  or  26  wherein said precursor is in linear form.  
     
     
         62 . A derivative of a molecule according to  claim 1  or  20 .  
     
     
         63 . A derivative according to  claim 62  wherein the derivative is a uncycle.  
     
     
         64 . A derivative according to  claim 62  or  63  wherein the derivative is a chemical analogue of the molecule.  
     
     
         65 . An antibody to a molecule defined in  claim 1  or  26 .  
     
     
         66 . An antibody according to  claim 65  wherein the antibody is a monoclonal antibody.  
     
     
         67 . Use of an isolated molecule according to  claim 1  or  26  and the manufacture of a medicament for the treatment or a prophylaxis of diseases in a mammal.  
     
     
         68 . Use according to  claim 67  wherein the mammal is a human.  
     
     
         69 . A method for the treatment or prophylaxis of a condition in a mammal, said method comprising administering a molecule according to  claim 1  or  26  and optionally having grafted thereon heterologous amino acids which confer an activity which prevent or treat said condition.  
     
     
         70 . A method according to  claim 69  wherein the activity of the heterologous amino acids modulates calcium channel-binding ability of C5a binding activity, proteinase inhibitor activity in plants or animals, antibiotic activity, HIV activity, plant pathogen activity, microbial activity, fungal activity, anti-viral activity, cytokine binding ability and/or blood clot inhibiting activity.  
     
     
         71 . A method according to  claim 69  wherein the activity of the heterologous amino acids exhibits therapeutic properties against cystic fibrosis.  
     
     
         72 . A topical composition useful in the prophylaxis or treatment of a disease or condition in a plant by a plant pathogen, said composition comprising a molecular framework according to  claim 1  or  26  and optionally having grafted thereto heterologous amino acids which confer anti-plant pathogen activity.  
     
     
         73 . A composition according to  claim 71  wherien the heterologous amino acids confer proteinase inhibitor activity.  
     
     
         74 . A composition according to  claim 71  wherein the composition inhibits an insect, spider, micro-organism, virus or fungus.  
     
     
         75 . A method of generating a molecule exhibiting a biological property or activity not normally associated with the naturally occurring molecule, said method comprising grafting onto said molecule one or more exogenous amino acid residues wherein said molecule comprises a sequence of amino acids or analogues thereof forming a cyclic backbone wherein the cyclic backbone comprises sufficient disulfide bonds or chemical equivalents thereof to confer knotted topology on the three-dimensional structure and having the following structure:— 
       
         
           
           
               
               
           
         
       
       wherein 
 C is cysteine;  
 each of [X 1  . . . X a ], [X I   1  . . . X I   b ], [X II   1  . . . X II   c ], [X III   1  . . . X III   d ], [X IV   1  . . . X IV   e ] and [X V   1  . . . X V   f ] represents one or more amino acid residues wherein each one or more amino acid residues within or between the sequence residues may be the same or different; and  
 wherein a, b, c, d, e and f represent the number of amino acid residues in each respective sequence and each of a to f may be the same or different and range from 1 to about 20;  
 or an analogue of said sequence.  
 
     
     
         76 . A method according to  claim 75  wherein the each of a to f ranges from about 1 to about 10.  
     
     
         77 . A method according to  claim 75  or  76  wherein a, b, c, d, e and f represent the number of amino acid residues in each respective sequence and wherein a is from about 3 to about 6, b is from about 3 to about 5, c is from about 2 to about 7, d is about 1 to about 3, e is about 3 to about 6 and f is from about 4 to about 9.  
     
     
         78 . A method according to  claim 75  or  76  wherein a, b, c, d, e and f represent the number of amino acid residues in each respective sequence and wherein a is about 3, b is about 4, c is from about 4 to about 7, d is about 1, e is about 4 or 5 and f is from about 4 to about 7.  
     
     
         79 . A method according to  claim 75  or  76  wherein a, b, c, d, e and f represent the number of amino acid residues in each respective sequence and wherein a is about 6, b is about 5, c is about 3, d is about 1, e is about 5 and f is about 8.  
     
     
         80 . A method according to  claim 75  wherein the cyclic backbone comprises at least two disulfide bonds.  
     
     
         81 . A method according to  claim 80  wherein the cyclic backbone comprises a cystine knot.  
     
     
         82 . A method according to  claim 81  wherein the cystine knot comprises at least three disulfide bonds.  
     
     
         83 . A method according to  claim 82  wherein the cystine knot comprises more than three disulfide bonds.  
     
     
         84 . A method according to  claim 75  wherein the molecule comprises a sequence set forth in <400>1.  
     
     
         85 . A method according to  claim 75  wherein the molecule comprises the sequence set forth in <400>2.  
     
     
         86 . A method according to  claim 75  wherein the molecule comprises the sequence set forth in <400>3.  
     
     
         87 . A method according to  claim 75  wherein the molecule comprises the sequence set forth in <400>4.  
     
     
         88 . A method according to  claim 75  wherein the molecule comprises the sequence set forth in <400>5.  
     
     
         89 . A method according to  claim 75  wherein the molecule comprises the sequence set forth in <400>6.  
     
     
         90 . A method according to  claim 75  wherein the molecule comprises the sequence set forth in <400>7.  
     
     
         91 . A method according to  claim 75  wherein the molecule comprises the sequence set forth in <400>8.  
     
     
         92 . A method according to  claim 75  wherein the molecule comprises the sequence set forth in <400>9.  
     
     
         93 . A method according to  claim 75  wherein the molecule comprises the sequence set forth in <400>10.  
     
     
         94 . A method according to  claim 75  wherein the molecule comprises the sequence set forth in <400>11.  
     
     
         95 . A method according to  claim 75  wherein the molecule comprises the sequence set forth in <400>12.  
     
     
         96 . A method according to  claim 75  wherein the molecule comprises the sequence set forth in <400>13.  
     
     
         97 . A method according to  claim 75  wherein the molecule comprises the sequence set forth in <400>19.  
     
     
         98 . A method according to  claim 75  wherein the molecule comprises the sequence set forth in <400>20.  
     
     
         99 . A method according to  claim 75  wherein the molecule comprises the sequence set forth in <400>21.

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