Cyclic peptides and uses thereof

Abstract

Cyclic D,L-α-peptides were shown to have an anti-amyloid aggregation effect. The cyclic peptide (designated cyclic peptide-2) having the sequence [1JwHsK], had a drastic effect on amyloid aggregation. However, the linear equivalent of cyclic peptide-2 did not inhibit amyloid formation. Cyclic peptide 2 was also effective in reducing Aβ-induced toxicity in PC12 cells. According to embodiments of the invention, cyclic peptides may comprise between 6 or 8 amino acids. In an embodiment, half of the amino acid residues are in the D-formation, and the other half are in the L-formation. In an embodiment of the invention, the amino acids alternate between the D and L-formations.

1 . A method for treating a disease associated with amyloid formation, comprising:
 administering to a patient in need thereof a cyclic peptide comprising alternating L- and D-amino acids.   
     
     
         2 . The method according to  claim 1  wherein the disease is selected from the group consisting of Alzheimer's disease, Lewy body dementia, cerebral amyloid angiopathy and inclusion body myositis, diabetes mellitus type 2, Parkinson's disease, transmissible spongiform encephalopathy, Huntington's disease, medullary carcinoma of the thyroid, isolated atrial amyloidosis, atherosclerosis, rheumatoid arthritis, prolactinomas, familial amyloid polyneuropathy, amyloidosis, lattice corneal dystrophy, systemic AL amyloidosis and inclusion body myositis. 
     
     
         3 . The method according to  claim 2  wherein the cyclic peptide has an even number of amino acids. 
     
     
         4 . The method according to  claim 3  wherein the cyclic peptide comprises 6 or 8 amino acids. 
     
     
         5 . The method according to  claim 1  wherein the cyclic peptide is composed of 6 amino acids, 3 of the amino acids in L-configuration and 3 of the amino acids in D-configuration. 
     
     
         6 . The method according to  claim 3  wherein the cyclic peptide is selected from the group consisting of cyclic peptides having the sequence:
 Cyclo-D-leucine-L-leucine-D-tryptophan-L-histidine-D-serine-L-lysine; 
 Cyclo-D-leucine-L-leucine-D-tryptophan-L-histidine-D-serine-L-alanine; 
 Cyclo-D-leucine-L-leucine-D-tryptophan-L-histidine-D-alanine-L-lysine; 
 Cyclo-D-leucine-L-leucine-D-tryptophan-L-alanine-D-serine-L-lysine; 
 Cyclo-D-leucine-L-leucine-D-alanine-L-histidine-D-serine-L-lysine; 
 Cyclo-D-leucine-L-alanine-D-tryptophan-L-histidine-D-serine-L-lysine; 
 Cyclo-D-alanine-L-leucine-D-tryptophan-L-histidine-D-serine-L-lysine; 
 Cyclo-D-leucine-L-norleucine-D-tryptophan-L-histidine-D-serine-L-lysine and 
 Cyclo-D-leucine-L-2-aminooctanoic acid-D-tryptophan-L-histidine-D-serine-L-lysine. 
 
     
     
         7 . The method according to  claim 1  wherein the disease associated with amyloid formation is associated with formation an amyloid comprising Aβ. 
     
     
         8 . The method according to  claim 1  wherein the disease associated with amyloid formation is associated with formation of an amyloid comprising a protein selected from the group consisting of: alpha-synuclein, Huntingtin and beta-2 microglobulin. 
     
     
         9 . The method according to  claim 1  wherein the cyclic peptide associates with an amyloid protein via hydrogen bonding, π-π and hydrophobic interactions. 
     
     
         10 . The method according to  claim 1  wherein the cyclic peptide induces one or more of:
 a conformational change to the structure of an amyloid protein; 
 an inhibition of aggregation of an amyloid protein; and 
 a reduction of concentration of toxic oligomers of an amyloid protein. 
 an inhibition of formation of amyloid fibrils. 
 
     
     
         11 . The method according to  claim 1  wherein the cyclic peptide is bound to a particle. 
     
     
         12 . A method of detecting amyloid plaques or aggregates in a subject, the method comprising:
 administering to the subject a cyclic peptide comprising alternating L- and D-amino acids and bound to a contrasting agent; and   detecting accumulations of the contrasting agent in the subject.   
     
     
         13 . The method according to  claim 12  wherein the cyclic peptide has an even number of amino acids. 
     
     
         14 . The method according to  claim 13  wherein the cyclic peptide comprises 6 or 8 amino acids. 
     
     
         15 . The method according to  claim 12  wherein the cyclic peptide is composed of 6 amino acids, 3 of the amino acids in L-configuration and 3 of the amino acids in D-configuration. 
     
     
         16 . The method according to  claim 15  wherein the cyclic peptide is selected from the group consisting of cyclic peptides having the sequence:
 Cyclo-D-leucine-L-leucine-D-tryptophan-L-histidine-D-serine-L-lysine; 
 Cyclo-D-leucine-L-leucine-D-tryptophan-L-histidine-D-serine-L-alanine; 
 Cyclo-D-leucine-L-leucine-D-tryptophan-L-histidine-D-alanine-L-lysine; 
 Cyclo-D-leucine-L-leucine-D-tryptophan-L-alanine-D-serine-L-lysine; 
 Cyclo-D-leucine-L-leucine-D-alanine-L-histidine-D-serine-L-lysine; 
 Cyclo-D-leucine-L-alanine-D-tryptophan-L-histidine-D-serine-L-lysine; 
 Cyclo-D-alanine-L-leucine-D-tryptophan-L-histidine-D-serine-L-lysine; 
 Cyclo-D-leucine-L-norleucine-D-tryptophan-L-histidine-D-serine-L-lysine and 
 Cyclo-D-leucine-L-2-aminooctanoic acid-D-tryptophan-L-histidine-D-serine-L-lysine. 
 
     
     
         17 . The method according to  claim 12  wherein the amyloid comprises an amyloid protein selected from the group consisting of: Aβ, alpha-synuclein, Huntingtin and beta-2 microglobulin. 
     
     
         18 . The method according to  claim 12  wherein the cyclic peptide is bound to a particle. 
     
     
         19 . The method according to  claim 12 , wherein the contrasting agent is selected from the group consisting of: a magnetite and a radioactive agent. 
     
     
         20 . The method according to  claim 19 , wherein the radioactive agent is Technetium-99 ( 99 Tc). 
     
     
         21 . The method according to  claim 12 , wherein the detection of the accumulations of the contrasting agent comprises subjecting the subject to magnetic resonance imaging (MRI) or computer tomography (CT) scanning.