Compositions Comprising D-Amino Acid Peptides and Methods of Production and Use Thereof for Inhibiting Autoantibodies

Abstract

Compositions are disclosed that include D-amino acid peptides and that are capable of specifically binding to at least one autoantibody against a G-protein coupled receptor. The autoantibody is produced in a patient having or being predisposed to a disease condition or disorder, and the autoantibody is capable of binding to a specific epitope of the G-protein coupled receptor. Methods of production and use of said compositions are also disclosed.

What is claimed is: 
     
         1 . A method of treating a subject having or predisposed to a disorder, condition, or disease involving an autoantibody against at least one target G-protein coupled receptor (GPCR), the method comprising the step of:
 administering to the subject a peptide composition comprising at least one retro-inverso D-amino acid (RID) peptide capable of specifically binding to the autoantibody, the at least one RID peptide comprising D-amino acids having a sequence that is a mirror image of at least a portion of a specific epitope of the at least one target GCPR such that the D-amino acids are in a reverse order compared to the native L-amino acid sequence of the specific epitope of the at least one target GPCR, whereby the at least one RID peptide of the peptide composition binds to the autoantibody causing a decrease in the binding of the autoantibody to the at least one target GPCR, and wherein the at least one target GPCR is selected from the group consisting of angiotensin II type 1 receptor (AT1R), angiotensin II type 2 receptor (AT2R), β1 adrenergic receptor (β1AR), β2 adrenergic receptor (β2AR), muscarinic acetylcholine receptor 2 (M2R), muscarinic acetylcholine receptor3 (M3R), α1 autonomic receptor (α1AR), dopamine receptor 1 (D1R), dopamine receptor 2 (D2R), thyroid stimulating hormone receptor (TSHR), β3-adrenergic receptor (β3AR), an endothelin receptor, and a thrombin receptor.   
     
     
         2 . The method of  claim 1  wherein the peptide composition comprises RID peptides which bind to autoantibodies against the group of target GPCRs consisting of α1AR, β1AR, AT1R, and M2R. 
     
     
         3 . The method of  claim 1 , wherein the disorder, condition, or disease is selected from the group consisting of hypertension, postural orthostatic tachycardia syndrome (POTS), idiopathic orthostatic hypotension, atrial fibrillation, tachycardia, bradycardia, tachyarrhythmia, cardiomyopathy, myocarditis, primary aldosteronism, idiopathic adrenal hyperplasia, aldosterone-producing adrenal adenoma, pediatric autoimmune neuropsychiatric disorder associated with Streptococcal infection (PANDAS), Raynaud's syndrome, hyperthyroidism, pre-eclampsia, and combinations thereof. 
     
     
         4 . A method of treating postural orthostatic tachycardia syndrome (POTS) in a subject in need of such treatment, the method comprising:
 administering to the subject a therapeutically-effective amount of at least one retro-inverso D-amino acid (RID) peptide capable of specifically binding to at least one autoantibody against α1 autonomic receptor (α1AR), β1 adrenergic receptor (β2AR), angiotensin II type 1 receptor (AT1R), or muscarinic acetylcholine receptor 2 (M2R), wherein the autoantibody is capable of binding to a specific epitope of the α1AR, β2AR, AT1R, or M2R, and wherein the at least one RID peptide comprises D-amino acids having a sequence that is a mirror image of at least a portion of the specific epitope such that the D-amino acids are in a reverse order compared to the native L-amino acid sequence of the specific epitope.   
     
     
         5 . The method of  claim 4 , wherein the specific epitope is positioned in a second extracellular loop (ECL2) of the α1AR. 
     
     
         6 . The method of  claim 4 , wherein the specific epitope comprises at least four consecutive amino acids of SEQ ID NO:16, and wherein the RID peptide comprises a sequence of D-amino acids in retro-inverso orientation to said at least four amino acids of SEQ ID NO:16. 
     
     
         7 . The method of  claim 4 , wherein the specific epitope comprises amino acids 10-14 of SEQ ID NO:16, and wherein the RID peptide comprises a sequence of D-amino acids in retro-inverso orientation to amino acids 10-14 of SEQ ID NO:16. 
     
     
         8 . The method of  claim 4 , wherein the RID peptide comprises at least five D-amino acids. 
     
     
         9 . The method of  claim 4 , wherein the peptide is orally administered to the subject. 
     
     
         10 . A method of treating postural orthostatic tachycardia syndrome (POTS) in a subject in need of such treatment, the method comprising:
 administering to the subject a therapeutically-effective amount of at least one retro-inverso D-amino acid (RID) peptide capable of specifically binding to at least one autoantibody against α1 autonomic receptor (α1AR), wherein the autoantibody is capable of binding to a specific epitope of the α1AR comprising at least four consecutive amino acids of SEQ ID NO:16, and the RID peptide comprising D-amino acids having a sequence that is a mirror image of at least a portion of the specific epitope such that the D-amino acids are in a reverse order compared to the native L-amino acid sequence of the specific epitope.   
     
     
         11 . The method of  claim 10 , wherein the specific epitope comprises amino acids 10-14 of SEQ ID NO:16, and wherein the RID peptide comprises a sequence of D-amino acids in retro-inverso orientation to amino acids 10-14 of SEQ ID NO:16. 
     
     
         12 . The method of  claim 10 , wherein the RID peptide comprises at least five D-amino acids. 
     
     
         13 . The method of  claim 10 , wherein the peptide is orally administered to the subject.