Targeting the neuromuscular junction for treatment
Compositions and methods for targeting therapeutic agents to neuromuscular junctions are disclosed. Also disclosed are methods for treating diseases and conditions affecting the neuromuscular junction. Compositions include a neuromuscular junction targeting peptide coupled to a therapeutic agent. Compositions may further include a linker peptide. Methods for targeting therapeutic agents to neuromuscular junctions and treating diseases and conditions affecting the neuromuscular junction include administering a composition including a neuromuscular junction targeting peptide coupled to a therapeutic agent.
1. A composition comprising a neuromuscular junction targeting peptide coupled to a therapeutic agent, wherein the neuromuscular junction targeting peptide is selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9 and wherein the therapeutic agent is selected from the group consisting of a complement inhibitor, an acetylcholinesterase inhibitor, and a trophic agent.
2. The composition of claim 1 , wherein the complement inhibitor is selected from the group consisting of decay accelerating factor, rEV encoded by SEQ ID NO: 10, rEV576, membrane cofactor protein, compstatin, a compstatin derivative, POT-4, a C1 inhibitor, C4b-binding protein, factor H, complement receptor Ig, CD59 (complement regulatory protein), clusterin, a C3-inhibitor, peptide 2J (SEQ ID NO: 36), human beta-defensin 2, CRIT-H17 (C2 receptor inhibitor trispanning-H17), Ac-SHLGLAR-H (SEQ ID NO: 37), Ac-RLLLAR-H (SEQ ID NO: 38), C1s-INH-248 (synthetic small molecule inhibitor of C1s), S-protein, Crry (complement receptor related protein), circumin, W-54011 (N-((4-Dimethylaminophenyl)methyl)-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-carboxamide), NDT9520492 ((2S)—N-(2,3-dihydro-1H-inden-2-yl)-N-[(2-fluorophenyl)methyl]-2-[(1R)-1-naphthalen-1-yl-3,4-dihydro-1H-isoquinolin-2-yl]propanamide), CP-447697 (4-{(1-Benzothiophen-3-ylcarbonyl)[2-(4-chlorophenyl)ethyl]amino}-N-(2,4-difluorophenyl)-1-piperidinecarboxamide), NDT 9513727 ([N,N-bis(1,3-benzodioxol-5-ylmethyl)-1-butyl-2,4-diphenyl-1H-imidazole-5-methanamine]), SB290157 (N 2 -[(2,2-Diphenylethoxy)acetyl]-L-arginine, SB290157(A) (arginine-substituted SB290157), SB290157(B) (aminopiperidine-derivative SB290157), BCX1470 (2-amidino-6-[2-thiophene carboxyl]benzothiophene methanesulfonate), PMX53 ((25)-2-acetamido-N-[(3S,9S,12S,15R,18S)-15-(cyclohexylmethyl)-9-[3-(diaminomethylideneamino)propyl]-12-(1H-indol-3-ylmethyl)-2,8,11,14,17-pentaoxo-1,7,10,13,16-pentazabicyclo[16.3.0]henicosan-3-yl]-3-phenylpropanamide), PMX205 (hydrocinnamic acid substituted derivative of PMX53), C089 (NMe-Phe-Lys-Pro-D-Cha-Trp-D-Arg-COOH), and JPE1375 (hydroorotic acid-Phe-Orn-Pro-(d-HomoLeu)-(4-Fluoro-Phe)-Phe).
3. The composition of claim 1 , further comprising a linker.
4. The composition of claim 3 , wherein the linker is selected from the group consisting of a glycine-serine linker, a peptide encoded by SEQ ID NO: 19, a peptide encoded by SEQ ID NO: 20, a peptide encoded by SEQ ID NO: 21, a peptide encoded by SEQ ID NO: 22, a peptide encoded by SEQ ID NO: 23, a peptide encoded by SEQ ID NO: 24, a peptide encoded by SEQ ID NO: 25, a peptide encoded by SEQ ID NO: 26, a peptide encoded by SEQ ID NO: 27, a peptide encoded by SEQ ID NO: 28, a peptide encoded by SEQ ID NO: 29, a peptide encoded by SEQ ID NO: 30, a peptide encoded by SEQ ID NO: 31, a peptide encoded by SEQ ID NO: 32, and a peptide encoded by SEQ ID NO: 33.
5. A method of delivering a therapeutic agent to the neuromuscular junction, the method comprising:
administering the composition according to claim 1 comprising a neuromuscular junction targeting peptide coupled to a therapeutic agent.
6. A composition comprising a neuromuscular junction targeting peptide coupled to a complement inhibitor, wherein the neuromuscular junction targeting peptide is selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9 and wherein the complement inhibitor is selected from the group consisting of decay accelerating factor, rEV encoded by SEQ ID NO: 10, rEV576, membrane cofactor protein, compstatin, a compstatin derivative, POT-4, a C1 inhibitor, C4b-binding protein, factor H, complement receptor Ig, CD59, clusterin, a C3-inhibitor, peptide 2J (SEQ ID NO: 36), human beta-defensin 2, CRIT-H17, Ac-SHLGLAR-H (SEQ ID NO: 37), Ac-RLLLAR-H (SEQ ID NO: 38), C1s-INH-248, S-protein, Crry, circumin, W-54011, NDT9520492, CP-447697, NDT 9513727, SB290157, SB290157(A), SB290157(B), BCX1470, PMX53, PMX205, C089, and JPE1375.
7. The composition of claim 6 , further comprising a linker.
8. The composition of claim 7 , wherein the linker is selected from the group consisting of a glycine-serine linker, a peptide encoded by SEQ ID NO: 19, a peptide encoded by SEQ ID NO: 20, a peptide encoded by SEQ ID NO: 21, a peptide encoded by SEQ ID NO: 22, a peptide encoded by SEQ ID NO: 23, a peptide encoded by SEQ ID NO: 24, a peptide encoded by SEQ ID NO: 25, a peptide encoded by SEQ ID NO: 26, a peptide encoded by SEQ ID NO: 27, a peptide encoded by SEQ ID NO: 28, a peptide encoded by SEQ ID NO: 29, a peptide encoded by SEQ ID NO: 30, a peptide encoded by SEQ ID NO: 31, a peptide encoded by SEQ ID NO: 32, and a peptide encoded by SEQ ID NO: 33.