Cyclic peptides and methods using same

1. A 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, Phe, Asp, Glu, and Ile;

Xaa 3 is selected from the group consisting of absent, Asn, Asp, and Glu;

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 2,4-diaminobutanoic acid, Orn, and Lys;

Xaa 9 is selected from the group consisting of absent, 2,4-diaminobutanoic acid, Orn, Lys, Glu, 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.

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 , and 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 , and Asp at Xaa 4 .

3. The cyclic compound of claim 1 , which is the cyclic compound of formula (II):

Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -P 1   (II),

wherein in (II):

Xaa 1 is selected from the group consisting of absent, Glu, and Arg;

Xaa 2 is selected from the group consisting of absent, Phe, Asp, Glu, and Ile;

Xaa 3 is selected from the group consisting of Asn, Asp, and Glu;

Xaa 4 is Asn;

Xaa 5 is Ile;

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, and metallocene;

Xaa 7 is Trp;

Xaa 8 is selected from the group consisting of 2,4-diaminobutanoic acid, Orn, and Lys;

Xaa 9 is selected from the group consisting of absent, 2,4-diaminobutanoic acid, Orn, Lys, Glu, 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 , and Asp at Xaa 3 ; 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.

4. The cyclic 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 cyclic compound of claim 1 , wherein P 1 is not absent.

6. The cyclic compound of claim 5 , 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 .

7. A cyclic compound, or a salt, solvate, enantiomer or diastereoisomer thereof, which is selected from the group consisting of:

8. The cyclic 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.

9. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one cyclic compound of claim 1 .

10. 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 .

11. The method of claim 10 , 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.

12. The method of claim 10 , wherein P 1 is not absent, wherein optionally (I) is complexed through the at least one thiol group with at least one gold nanoparticle.