Cyclic peptides, cyclic peptide conjugates and methods of use thereof

1. A conjugate comprising a cyclic peptide of SEQ ID NO: 6

conjugated to (X) m at the N-terminal end, wherein (X) m , is an opioid receptor ligand or analogue thereof present in the central nervous system or a pharmaceutically acceptable salt thereof, and wherein the residues Xaa at positions 8-12 of SEQ ID NO: 6 consist of an opioid receptor ligand or analogue thereof present in the central nervous system or a pharmaceutically acceptable salt thereof, and

wherein the conjugate has antinociceptive and analgesic activity.

2. The conjugate of claim 1 , wherein the opioid receptor ligand is a δ opioid receptor (DOR) antagonist, a DOR agonist, a μ opioid receptor (MOR) antagonist, a MOR agonist, a κ opioid receptor (KOR) antagonist, or a KOR agonist.

3. The conjugate of claim 1 , wherein the conjugate modulates opioid receptor activity.

4. A cyclic peptide comprising the amino acid sequence selected from the group consisting of

(SEQ ID NO: 8)

DADLE-OL = Y 1 A 2 S 3 P 4 K 5 - cyclo [C 6 F 7 R 8 Y 9 a 10 G 11 F 12 I 13

L 14 A 15 C 16 ]T 17 ;

(SEQ ID NO: 9)

DADLE-OL II = Y 1 a 2 G 3 F 4 I 5 K 6 - cyclo [C 7 F 8 R 9 Y 10 P 11 N 12

G 13 V 14 L 15 A 16 C 17 ]T 18 ;

(SEQ ID NO: 10)

TIPP-OL = Y 1 A 2 S 3 P 4 K 5 - cyclo [C 6 F 7 R 8 Y 9 Tic 10 F 11 F 12 V 13

L 14 A 15 C 16 ]T 17 ;

(SEQ ID NO: 7)

TIPP-EM1-OL. = Y 1 P 2 W 3 F 4 K 5 - cyclo [C 6 F 7 R 8 Y 9 Tic 10 F 11

F 12 V 13 L 14 A 15 C 16 ]T 17 ;

(SEQ ID NO: 11)

OLKOR-L1 = Y 1 A 2 S 3 P 4 K 5 - cyclo [C 6 F 7 R 8 G 9 F 10 W 11 P 12 K 13

L 14 A 15 C 16 ]T 17 ;

and

(SEQ ID NO: 12)

OLMOR-L1 = Y 1 A 2 S 3 P 4 K 5 - cyclo [C 6 F 7 R 8 H 9 F 10 P 11 V 12 N 13

L 14 A 15 C 16 ]T 17 ,

wherein a=D-Ala and 1=D-Leu.

5. The conjugate of claim 1 , wherein a therapeutic agent is conjugated to (X) m .

6. The conjugate of claim 5 , wherein the therapeutic agent is a small molecule.

7. The conjugate of claim 5 , wherein the therapeutic agent is selected from the group consisting of an analgesic, an anti-convulsant, an antidote, an anti-microbial, an anti-cancer, an anti-inflammatory, and an anti-neurodegenerative.

8. The conjugate of claim 6 , wherein the small molecule is selected from the group consisting of 5-hydroxytryptophan (5HTrp), naloxone, serotonin, dopamine, L-3,4-dihydroxyphenylalanine (L-DOPA), epinephrine, norepinephrine, histamine, adenosine triphosphate, adenosine, cannabidiol (CBD), CBD derivative, tetrahydrocannabinol (THC), THC derivative, selective serotonin reuptake inhibitor, serotonin— norepinephrine reuptake inhibitor (SNRI), memantine, and pramipexole.

9. A cyclic peptide conjugate comprising the amino acid sequence:

5-HTrp 1 -A 2 S 3 P 4 K 5 -cyclo[C 6 F 7 R 8 G 9 F 10 W 11 P 12 K 13 L 14 A 15 C 16 ]T 17 (SEQ ID NO: 13).

10. The conjugate of claim 5 , wherein the therapeutic agent is a protein.

11. The conjugate of claim 10 , wherein the protein is a growth hormone.

12. The conjugate of claim 5 , wherein the therapeutic agent is an opioid receptor ligand or analogue thereof.

13. The conjugate of claim 12 , wherein the opioid receptor ligand is a DOR antagonist, a DOR agonist, a MOR antagonist a MOR agonist, a KOR antagonist, or a KOR agonist.

14. A conjugate comprising a cyclic peptide of SEQ ID NO: 16 having conjugated to its N-terminus a therapeutic agent, wherein the therapeutic agent is conjugated to the N-terminus via a cleavable bond or linker.

15. The conjugate of claim 14 , wherein the therapeutic agent is a small molecule selected from the group consisting of 5HTrp, naloxone, serotonin, dopamine, L-DOPA, epinephrine, norepinephrine, histamine, adenosine triphosphate, adenosine, cannabidiol (CBD), CBD derivative, tetrahydrocannabinol (THC), THC derivative, nabilone, selective serotonin reuptake inhibitor, fluvoxamine, serotonin-norepinephrine reuptake inhibitor (SNRI), desvenlafaxine, milnacipran, levomilnacipran, memantine, and pramipexole.

16. A cyclic peptide conjugate comprising the sequence

SEQ ID NO: 17.

17. A composition for intranasal administration comprising a therapeutically effective amount of the conjugate of claim 1 and a pharmaceutically acceptable carrier.

18. A method of treating pain in an individual comprising administering to the individual in need thereof a composition comprising a cyclic peptide comprising the amino acid sequence of SEQ ID NO: 11 or SEQ ID NO: 13 via intranasal delivery to the individual's brain.

19. The method of claim 18 , wherein the pain is neuropathic pain.

20. A conjugate comprising a cyclic peptide of SEQ ID NO: 6

conjugated to a small molecule,

wherein the residues Xaa at positions 8-12 of SEQ ID NO: 6 consist of an opioid receptor ligand or analogue thereof present in the central nervous system or a pharmaceutically acceptable salt thereof, and

wherein the conjugate has antinociceptive and analgesic activity, and

wherein the small molecule is selected from the group consisting of nabilone, fluvoxamine, desvenlafaxine, milnacipran, and levomilnacipran.

21. A conjugate comprising a cyclic peptide of SEQ ID NO: 16 having directly conjugated to its N-terminus a therapeutic agent.

22. The conjugate of claim 21 , wherein the therapeutic agent is a small molecule selected from the group consisting of 5HTrp, naloxone, serotonin, dopamine, L-DOPA, epinephrine, norepinephrine, histamine, adenosine triphosphate, adenosine, cannabidiol (CBD), CBD derivative, tetrahydrocannabinol (THC), THC derivative, nabilone, selective serotonin reuptake inhibitor, fluvoxamine, serotonin-norepinephrine reuptake inhibitor (SNRI), desvenlafaxine, milnacipran, levomilnacipran, memantine, and pramipexole.

23. The conjugate of claim 21 , wherein the therapeutic agent is a peptide.