Cyclic Peptide Antiviral Agents 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.

What is claimed: 
     
         1 . A cyclic compound of formula (I), or a salt, solvate, enantiomer or diastereoisomer thereof: 
       
         
           
                 
                 
               
                     
                   (I) 
                 
                     
                   Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -P 1 , 
                 
             
                
                
               
            
           
         
         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, butanedioic acid, 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 R III  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 IV  is selected from the group consisting of: adamantyl substituted with 0-2 C 1 -C6 alkyl groups; —(C 0 -C 4  alkyl) phenyl, wherein the phenyl is substituted with 0-2 C 1 -C 6  alkyl groups; phenyl substituted with R 1  and with 0-2 C 1 -C 6  alkyl groups; and heteroaryl substituted with R 1  and with 0-2 C 1 -C 6  alkyl groups;
 wherein each occurrence of R 1  is independently selected from the group consisting of phenyl substituted with 0-2 C 1 -C 6  alkyl groups and heteroaryl substituted with 0-2 C 1 -C 6  alkyl groups; and 
 wherein each occurrence of heteroaryl is independently selected from the group consisting of pyridine, pyrimidine, thiophene, furan, pyrrole, imidazole, oxazole, oxadiazole, thiazole, thiadiazolyl, isothiazole, and tetrazole; 
     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 , succinic acid 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.   
 
     
     
         2 . The cyclic compound of  claim 1 , which is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein in (Ia)-(If) ‘NH’ is derived from the side chain amino group of a 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 , and 
         ‘C═O’ is derived from the side chain carboxylic acid group of a residue selected from the group consisting of Glu at Xaa 2 , Asp at Xaa 2 , Glu at Xaa 3 , Asp at Xaa 3 , succinic acid at Xaa 3 , and Asp at Xaa 4.    
       
     
     
         3 . The cyclic compound of  claim 1 , which is the cyclic compound of formula (II): 
       
         
           
                 
                 
               
                     
                   (II) 
                 
                     
                   Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -P 1 , 
                 
             
                
                
               
            
           
         
         wherein in (II):
 Xaa 3  is selected from the group consisting of Asn, Asp, succinic acid, and Glu; 
 Xaa 4  is Asn; 
 Xaa 5  is Ile; and 
 Xaa 7  is Trp. 
 
       
     
     
         4 . The compound of  claim 1 , wherein Xaa 5  is selected from the group consisting of Ile, Leu, norleucine (Nle), cyclopropylglycine, cyclobutylglycine, cyclopentylglycine, and cyclohexylglycine. 
     
     
         5 . The compound of  claim 1 , wherein R III  is a secondary or tertiary hydrocarbyl group. 
     
     
         6 . The compound of  claim 5 , wherein R III  is selected from the group consisting of cyclohexyl, —CH(CH 3 )(C 1 -C 4  alkyl), and —C(CH 3 ) 2 (C 1 -C 3  alkyl). 
     
     
         7 . The compound of  claim 1 , wherein the C-terminus of Xaa 8  is not amidated if Xaa 9  and P 1  are absent, or wherein the C-terminus of Xaa 9  is not amidated if P 1  is absent. 
     
     
         8 . The compound of  claim 1 , wherein the C-terminus of Xaa 8  is amidated if Xaa 9  and P 1  are absent, or wherein the C-terminus of Xaa 9  is amidated if P 1  is absent. 
     
     
         9 . The compound of  claim 1 , wherein, if the carbon alpha to the carboxyl group of Xaa 8  is chiral, the stereochemistry of the alpha carbon is S. 
     
     
         10 . The compound of  claim 1 , wherein in (IV) the heteroaryl is thiophene. 
     
     
         11 . The compound of  claim 1 , wherein R IV  is selected from the group consisting of:
 —(C 0 -C 4  alkyl) phenyl, wherein the phenyl is substituted with 1-2 C 1 -C 6  alkyl groups, wherein one of the C 1 -C 6  alkyl groups is at the para position of the phenyl group;   
       
         
           
           
               
               
           
         
         wherein each occurrence of R 1  is independently C 1 -C 6  alkyl; m is 0, 1, or 2; and n is 0 or 1. 
       
     
     
         12 . The compound of  claim 1 , wherein P 1  is not absent. 
     
     
         13 . The compound of  claim 12 , wherein P 1  comprises at least one cysteine residue. 
     
     
         14 . The compound of  claim 12 , wherein P 1  is selected from the group consisting of 
       
         
           
                 
                 
               
                     
                   βAla Gln βAla Cys-NH 2 , βAla Gln βAla Cys, 
                 
                     
                     
                 
                     
                   NH 2 (CH 2 CH 2 O) 0-10 CH 2 C(═O)NHCH(CH 2 SH)C(═O)OH, 
                 
                     
                     
                 
                     
                   NH 2 (CH 2 CH 2 O) 0-10 CH 2 C(═O)NHCH(CH 2 SH)C(═O)NH 2 , 
                 
                     
                     
                 
                     
                   NH 2 (CH 2 ) 0-12 CH 2 C(═O)NHCH(CH 2 SH)C(═O)OH, 
                 
                     
                     
                 
                     
                   NH 2 (CH 2 ) 0-12 CH 2 C(═O)NHCH(CH 2 SH)C(═O)NH 2 , 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   NH 2 CH 2 CH 2 OCH 2 CH 2 OC(═O)NHCH(CH 2 SH)C(═O)NH 2 . 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         15 . The compound of  claim 1 , which is selected from the group consisting of:
 29N-2 or 36 [also known as (3S,6S,14S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-14-amino-17-(2-amino-2-oxoethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide]   
       
         
           
           
               
               
           
         
         37 [also known as (3S,6S,14S,17S,20S,24S,25aS)-3-1H-indol-3-yl)methyl)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-14-amino-17-(2-amino-2-oxoethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide] 
       
       
         
           
           
               
               
           
         
         38 [also known as (3S,6S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-17-(2-amino-2-oxoethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl) phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13, 18]hexaazacyclotricosine-6-carboxamide] 
       
       
         
           
           
               
               
           
         
         (3S,6S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-17-(2-amino-2-oxoethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,14][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,14S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-14-amino-17-(2-amino-2-oxoethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3 -triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18] hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,14S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-14-amino-17-(2-amino-2-oxoethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18] hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-17-(2-amino-2-oxoethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-17-(2-amino-2-oxoethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,14S,17S,20S,24S,25aS)-14-amino-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl) phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13, 18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,14S,17S,20S,24S,25aS)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-14-amino-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,17S,20S,24S,25aS)-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,17S,20S,24S,25aS)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,14S,17S,20S,24S,25aS)-14-amino-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H -1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         ((3S,6S,14S,17S,20S,24S,25aS)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-14-amino-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,17S,20S,24S,25aS)-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         (3S,6S,17S,20S,24S,25aS)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide 
       
       
         
           
           
               
               
           
         
         or a salt or solvate thereof. 
       
     
     
         16 . The compound of  claim 1 , which is a compound of formula (V): 
       
         
           
           
               
               
           
         
         wherein: 
         R a  is NH 2  or H; 
         R b  is cyclohexyl or sec-butyl; 
         R c  is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R d  is NH or S; 
         or a salt or solvate thereof. 
       
     
     
         17 . The compound of  claim 1 , wherein P 1  is not absent and wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle. 
     
     
         18 . The compound of  claim 17 , wherein the at least one nanoparticle has an average diameter of about 20 nm. 
     
     
         19 . A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one cyclic compound of  claim 1 . 
     
     
         20 . The composition of  claim 19 , wherein P 1  in (I) is not absent and wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle. 
     
     
         21 . The composition of  claim 19 , further comprising at least one additional compound useful for treating viral infections. 
     
     
         22 . The composition of  claim 21 , wherein the at least one additional compound is selected from the group consisting of antiviral combination drugs, entry and fusion inhibitors, integrase inhibitors, non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, protease inhibitors, and any combinations thereof. 
     
     
         23 . The composition of  claim 19 , wherein the peptide is encapsulated in a hydrogel and/or liposome. 
     
     
         24 . 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  claim 1 . 
     
     
         25 . The method of  claim 24 , wherein the compound is at least one compound of  claim 15  or  16 , or a salt or solvate thereof. 
     
     
         26 . The method of  claim 24 , wherein P 1  is not absent. 
     
     
         27 . The method of  claim 26 , wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle. 
     
     
         28 . The method of  claim 24 , wherein the mammal is further administered at least one additional compound useful for treating viral infections. 
     
     
         29 . The method of  claim 24 , wherein the mammal is human. 
     
     
         30 . A method of reducing the risk of HIV-1 infection in a mammal at risk of HIV-1 exposure, the method comprising administering to the mammal a therapeutically effective amount of at least one cyclic compound of  claim 1 . 
     
     
         31 . The method of  claim 30 , wherein the compound is at least one compound of  claim 15  or 16, or a salt or solvate thereof. 
     
     
         32 . The method of  claim 30 , wherein P 1  is not absent. 
     
     
         33 . The method of  claim 32 , wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle. 
     
     
         34 . The method of  claim 30 , wherein the mammal is further administered at least one additional compound useful for treating viral infections. 
     
     
         35 . The method of  claim 30 , wherein the mammal is human. 
     
     
         36 . 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  claim 1 , wherein P 1  is not absent. 
     
     
         37 . The method of  claim 36 , wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle. 
     
     
         38 . The method of  claim 36 , wherein the virus comprises HIV-1. 
     
     
         39 . 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  claim 1 . 
     
     
         40 . The method of  claim 39 , wherein the compound is at least one compound of  claim 15  or  16 , or a salt or solvate thereof. 
     
     
         41 . The method of  claim 39 , wherein P 1  is not absent. 
     
     
         42 . The method of  claim 41 , wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle. 
     
     
         43 . The method of  claim 39 , wherein the virus comprises HIV-1. 
     
     
         44 . The method of  claim 39 , wherein the mammal is human. 
     
     
         45 . A method of preparing a derivatized gold nanoparticle, the method comprising contacting the nanoparticle with at least one cyclic compound of  claim 1  to generate a reaction system; and isolating the derivatized gold nanoparticle from the reaction system.