Cyclic Peptides and Methods Using Same

Abstract

The present invention includes novel cyclic peptides, and methods of using the same. The present invention further includes novel cyclic peptides conjugated with a gold nanoparticle, and methods of using the same.

1 - 25 . (canceled) 
     
     
         26 . A method of treating, reducing or preventing HIV-1 infection in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of at least one cyclic compound of formula (I), or a salt, solvate, enantiomer or diastereoisomer thereof:
   Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -P 1   (I),
   wherein in (I):
 Xaa 1  is selected from the group consisting of absent, Glu and Arg; 
 Xaa 2  is selected from the group consisting of absent, Gly, Phe, Lys, Asp, Glu, Ile, Arg and Cit; 
 Xaa 3  is selected from the group consisting of absent, Asn, Asp, Ile, Glu and 2-cyclohexylglycine; 
 Xaa 4  is selected from the group consisting of Asn and Asp; 
 Xaa 5  is a modified glycine of formula (III) 
   
       
         
           
           
               
               
           
         
         
            wherein in (III) R is selected from the group consisting of C 1 -C 6  alkyl and C 3 -C 6  cycloalkyl; 
           Xaa 6  is the modified proline of formula (IV) 
         
       
       
         
           
           
               
               
           
         
         
            wherein in (IV) R is selected from the group consisting of naphthyl, p-methyl phenyl, p-ethyl phenyl, 2-phenylethyl, 1-adamantyl, 2-adamantyl and metallocene; 
           Xaa 7  is selected from the group consisting of Trp and 3-(3-benzothienyl)-L-alanine; 
           Xaa 8  is selected from the group consisting of Ser, Thr, 2,4-diaminobutanoic acid, Orn and Lys; 
           Xaa 9  is selected from the group consisting of absent, 2,4-diaminobutanoic acid, Orn, Lys, Glu, Glu-Ala, Glu-Ala-Met, Glu-Ala-Met-Met, and 2-(2-(2-aminoethoxy)ethoxy)acetic acid; 
           P 1  is absent, or is a group that comprises at least one thiol group and is covalently linked through an amide bond to (i) the C-terminus of Xaa 9  if Xaa 9  is not absent, or (ii) the C-terminus of Xaa 8  if Xaa 9  is absent; 
           the side chain amino group of one residue selected from the group consisting of 2,4-diaminobutanoic acid at Xaa 8 , Orn at Xaa 8 , Lys at Xaa 8 , 2,4-diaminobutanoic acid at Xaa 9 , Orn at Xaa 9 , and Lys at Xaa 9  forms an amide bond with the side chain carboxylic acid group of one residue selected from the group consisting of Glu at Xaa 2 , Asp at Xaa 2 , Glu at Xaa 3 , Asp at Xaa 3  and Asp at Xaa 4 ; and 
           the C-terminus of Xaa 8  is optionally amidated if Xaa 9  and P 1  are absent, or the C-terminus of Xaa 9  is optionally amidated if P 1  is absent. 
         
       
     
     
         27 . The method of  claim 26 , wherein the compound is selected from the group consisting of AAR024, AAR026, AAR029, AAR030, AAR031, AAR032, AAR024B, AAR029B, AAR029b-Chg, AAR029E, AAR036, AAR029F, AAR029H, AAR040 and AAR042. 
     
     
         28 . The method of  claim 26 , wherein the compound is selected from the group consisting of AAR024, AAR026 and AAR029. 
     
     
         29 . The method of  claim 26 , wherein P 1  is not absent. 
     
     
         30 . The method of  claim 29 , wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle. 
     
     
         31 . The method of  claim 26 , wherein the mammal is further administered at least one additional compound useful for treating viral infections. 
     
     
         32 . The method of  claim 26 , wherein the mammal is human. 
     
     
         33 - 39 . (canceled) 
     
     
         40 . A method of promoting virolysis of a virus, the method comprising contacting the virus with an effective amount of at least one cyclic compound of formula (I), or a salt, solvate, enantiomer or diastereoisomer thereof:
   Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -P 1   (I),
   wherein in (I):
 Xaa 1  is selected from the group consisting of absent, Glu and Arg; 
 Xaa 2  is selected from the group consisting of absent, Gly, Phe, Lys, Asp, Glu, Ile, Arg and Cit; 
 Xaa 3  is selected from the group consisting of absent, Asn, Asp, Ile, Glu and 2-cyclohexylglycine; 
 Xaa 4  is selected from the group consisting of Asn and Asp; 
 Xaa 5  is a modified glycine of formula (III) 
   
       
         
           
           
               
               
           
         
         
            wherein in (III) R is selected from the group consisting of C 1 -C 6  alkyl and C 3 -C 6  cycloalkyl; 
           Xaa 6  is the modified proline of formula (IV) 
         
       
       
         
           
           
               
               
           
         
         
            wherein in (IV) R is selected from the group consisting of naphthyl, p-methyl phenyl, p-ethyl phenyl, 2-phenylethyl, 1-adamantyl, 2-adamantyl and metallocene; 
           Xaa 7  is selected from the group consisting of Trp and 3-(3-benzothienyl)-L-alanine; 
           Xaa 8  is selected from the group consisting of Ser, Thr, 2,4-diaminobutanoic acid, Orn and Lys; 
           Xaa 9  is selected from the group consisting of absent, 2,4-diaminobutanoic acid, Orn, Lys, Glu, Glu-Ala, Glu-Ala-Met, Glu-Ala-Met-Met, and 2-(2-(2-aminoethoxy)ethoxy)acetic acid; 
           P 1  is a group that comprises at least one thiol group and is covalently linked through an amide bond to (i) the C-terminus of Xaa 9  if Xaa 9  is not absent, or (ii) the C-terminus of Xaa 8  if Xaa 9  is absent; 
           the side chain amino group of one residue selected from the group consisting of 2,4-diaminobutanoic acid at Xaa 8 , Orn at Xaa 8 , Lys at Xaa 8 , 2,4-diaminobutanoic acid at Xaa 9 , Orn at Xaa 9 , and Lys at Xaa 9  forms an amide bond with the side chain carboxylic acid group of one residue selected from the group consisting of Glu at Xaa 2 , Asp at Xaa 2 , Glu at Xaa 3 , Asp at Xaa 3  and Asp at Xaa 4 . 
         
       
     
     
         41 . The method of  claim 40 , wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle. 
     
     
         42 . The method of  claim 40 , wherein the virus comprises HIV-1. 
     
     
         43 . A method of reducing the rate of or preventing entry of a virus into a cell of a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one cyclic compound of formula (I), or a salt, solvate, enantiomer or diastereoisomer thereof:
   Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -P 1   (I),
   wherein in (I):
 Xaa 1  is selected from the group consisting of absent, Glu and Arg; 
 Xaa 2  is selected from the group consisting of absent, Gly, Phe, Lys, Asp, Glu, Ile, Arg and Cit; 
 Xaa 3  is selected from the group consisting of absent, Asn, Asp, Ile, Glu and 2-cyclohexylglycine; 
 Xaa 4  is selected from the group consisting of Asn and Asp; 
 Xaa 5  is a modified glycine of formula (III) 
   
       
         
           
           
               
               
           
         
         
            wherein in (III) R is selected from the group consisting of C 1 -C 6  alkyl and C 3 -C 6  cycloalkyl; 
           Xaa 6  is the modified proline of formula (IV) 
         
       
       
         
           
           
               
               
           
         
         
            wherein in (IV) R is selected from the group consisting of naphthyl, p-methyl phenyl, p-ethyl phenyl, 2-phenylethyl, 1-adamantyl, 2-adamantyl and metallocene; 
           Xaa 7  is selected from the group consisting of Trp and 3-(3-benzothienyl)-L-alanine; 
           Xaa 8  is selected from the group consisting of Ser, Thr, 2,4-diaminobutanoic acid, Orn and Lys; 
           Xaa 9  is selected from the group consisting of absent, 2,4-diaminobutanoic acid, Orn, Lys, Glu, Glu-Ala, Glu-Ala-Met, Glu-Ala-Met-Met, and 2-(2-(2-aminoethoxy)ethoxy)acetic acid; 
           P 1  is absent, or is a group that comprises at least one thiol group and is covalently linked through an amide bond to (i) the C-terminus of Xaa 9  if Xaa 9  is not absent, or (ii) the C-terminus of Xaa 8  if Xaa 9  is absent; 
           the side chain amino group of one residue selected from the group consisting of 2,4-diaminobutanoic acid at Xaa 8 , Orn at Xaa 8 , Lys at Xaa 8 , 2,4-diaminobutanoic acid at Xaa 9  Orn at Xaa 9 , and Lys at Xaa 9  forms an amide bond with the side chain carboxylic acid group of one residue selected from the group consisting of Glu at Xaa 2 , Asp at Xaa 2 , Glu at Xaa 3 , Asp at Xaa 3  and Asp at Xaa 4 ; and 
         
         the C-terminus of Xaa 8  is optionally amidated if Xaa 9  and P 1  are absent, or the C-terminus of Xaa 9  is optionally amidated if P 1  is absent. 
       
     
     
         44 . The method of  claim 43 , wherein the compound is selected from the group consisting of AAR024, AAR026, AAR029, AAR030, AAR031, AAR032, AAR024B, AAR029B, AAR029b-Chg, AAR029E, AAR036, AAR029F, AAR029H, AAR040 and AAR042. 
     
     
         45 . The method of  claim 43 , wherein the compound is selected from the group consisting of AAR024, AAR026 and AAR029. 
     
     
         46 . The method of  claim 43 , wherein P 1  is not absent. 
     
     
         47 . The method of  claim 46 , wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle. 
     
     
         48 . The method of  claim 43 , wherein the virus comprises HIV-1. 
     
     
         49 . The method of  claim 43 , wherein the mammal is human. 
     
     
         50 . A method of preparing a derivatized gold nanoparticle, the method comprising contacting the nanoparticle with at least one cyclic compound of formula (I), or a salt, solvate, enantiomer or diastereoisomer thereof, to generate a reaction system; and isolating the derivatized gold nanoparticle from the reaction system:
 wherein the compound of formula (I) is:
   Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -P 1   (I),
 
   wherein:
 Xaa 1  is selected from the group consisting of absent, Glu and Arg; 
 Xaa 2  is selected from the group consisting of absent, Gly, Phe, Lys, Asp, Glu, Ile, Arg and Cit; 
 Xaa 3  is selected from the group consisting of absent, Asn, Asp, Ile, Glu and 2-cyclohexylglycine; 
 Xaa 4  is selected from the group consisting of Asn and Asp; 
 Xaa 5  is a modified glycine of formula (III) 
   
       
         
           
           
               
               
           
         
         
            wherein in (III) R is selected from the group consisting of C 1 -C 6  alkyl and C 3 -C 6  cycloalkyl; 
           Xaa 6  is the modified proline of formula (IV) 
         
       
       
         
           
           
               
               
           
         
         
            wherein in (IV) R is selected from the group consisting of naphthyl, p-methyl phenyl, p-ethyl phenyl, 2-phenylethyl, 1-adamantyl, 2-adamantyl and metallocene; 
           Xaa 7  is selected from the group consisting of Trp and 3-(3-benzothienyl)-L-alanine; 
           Xaa 8  is selected from the group consisting of Ser, Thr, 2,4-diaminobutanoic acid, Orn and Lys; 
           Xaa 9  is selected from the group consisting of absent, 2,4-diaminobutanoic acid, Orn, Lys, Glu, Glu-Ala, Glu-Ala-Met, Glu-Ala-Met-Met, and 2-(2-(2-aminoethoxy)ethoxy)acetic acid; 
           P 1  is absent, or is a group that comprises at least one thiol group and is covalently linked through an amide bond to (i) the C-terminus of Xaa 9  if Xaa 9  is not absent, or (ii) the C-terminus of Xaa 8  if Xaa 9  is absent; 
           the side chain amino group of one residue selected from the group consisting of 2,4-diaminobutanoic acid at Xaa 8 , Orn at Xaa 8 , Lys at Xaa 8 , 2,4-diaminobutanoic acid at Xaa 9  Orn at Xaa 9 , and Lys at Xaa 9  forms an amide bond with the side chain carboxylic acid group of one residue selected from the group consisting of Glu at Xaa 2 , Asp at Xaa 2 , Glu at Xaa 3 , Asp at Xaa 3  and Asp at Xaa 4 ; and 
         
         the C-terminus of Xaa 8  is optionally amidated if Xaa 9  and P 1  are absent, or the C-terminus of Xaa 9  is optionally amidated if P 1  is absent.