Non-cleavable substance p conjugates and methods of use thereof

Abstract

Described herein are methods for treating disorders that relate to neurons that express the neurokinin-1 receptor (NK-1R) in a subject which comprises administering to the subject an effective amount of the pharmaceutical composition of the non-cleavable conjugate comprising a molecule that is recognized and internalized by the NK-1R, and a molecule that is taken inside the cell to kill or temporarily alter the cell.

1 - 17 . (canceled) 
     
     
         18 . A composition, wherein the composition comprising a non-cleavable conjugate comprising:
 a) a first molecule that binds to a neurokinin-1 receptor, wherein the first molecule comprises substance P analog; and   b) a second molecule that is taken inside a cell to alter the cell via binding to the neurokinin-1 receptor.   
     
     
         19 . The composition of  claim 18 , wherein the non-cleavable conjugate further comprises a non-peptidic sequence. 
     
     
         20 . The composition of  claim 19 , wherein the non-peptidic sequence is Maleimidopropionic acid (MPA)amino-ethoxy-ethoxy acetic acid (AEEAc). 
     
     
         21 . The composition of  claim 18 , wherein the first molecule comprises a Substance P or an analog thereof. 
     
     
         22 . The composition of  claim 21 , wherein the Substance P or the analog thereof is selected from the group consisting of (Maleimidopropionic acid MPA)GGGGGGRPKPQQFFSarLMet(O.sub.2)-amide (SEQ ID No.:1) and Maleimidopropionic acid (MPA)GGGGGGRPKPQQFFGLM-amide (SEQ ID No.:2). 
     
     
         23 . The composition of  claim 18 , wherein the second molecule comprises a toxin. 
     
     
         24 . The composition of  claim 23 , wherein the toxin is selected from the group consisting of botulinum toxin or fragment thereof, diphtheria toxin A fragment or an analog thereof, pseudomonas aeruginosa exotoxin A fragment or an analog thereof that inhibits protein synthesis, and any combinations thereof. 
     
     
         25 . The composition of  claim 24 , wherein the toxin is botulinum toxin or fragment thereof. 
     
     
         26 . The composition of  claim 18 , wherein the second molecule comprises a ribosome-inactivating protein. 
     
     
         27 . The composition of  claim 25 , wherein the ribosome-inactivating protein is selected from saporin, ricin A chain, gelonin, pokeweed antiviral protein, and any combinations thereof. 
     
     
         28 . The composition of  claim 18 , wherein the second molecule comprises maytansinoid or auristatin. 
     
     
         29 . The composition of  claim 25 , wherein the non-cleavable conjugate has a structure of SP(MAP)- botulinum toxin or fragment thereof. 
     
     
         30 . The composition of claim  12 , wherein MAP is located at the N-terminus of the botulinum toxin or fragment thereof. 
     
     
         31 . The composition of  claim 29 , wherein the structure further comprises a spacer between MAP and botulinum toxin or fragment thereof. 
     
     
         32 . The composition of  claim 31 , wherein the space prevents steric hinderance wherein when the non-cleavable conjugate binds to the neurokinin-1 receptor. 
     
     
         33 . The composition of  claim 29 , wherein the non-cleavable conjugate maintains its cell altering activity. 
     
     
         34 . The composition of  claim 30 , wherein the cell altering activity comprises killing the cell. 
     
     
         35 . A pharmaceutical composition comprising a therapeutically effective amount of the conjugate of  claim 18  and a pharmaceutically acceptable carrier. 
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein the pharmaceutical composition is in a topical formulation. 
     
     
         37 . The pharmaceutical composition of  claim 36 , wherein the topical formulation comprises gels, creams, solutions, emulsions, carbohydrate polymers, biodegradable matrices of the carbohydrate polymers, vapors, mists, aerosols, or other inhalants. 
     
     
         38 . The pharmaceutical composition of  claim 35 , wherein the pharmaceutical composition is in a solid formulation. 
     
     
         39 . The pharmaceutical composition of  claim 38 , wherein the solid formulation comprises pills, capsules, granules, tablets, or powder. 
     
     
         40 . The pharmaceutical composition of  claim 35 , wherein the pharmaceutical composition is in a liquid formulation. 
     
     
         41 . The pharmaceutical composition of  claim 40 , wherein the liquid formulation comprises solutions, syrups, elixirs, or suspensions. 
     
     
         42 . A method for treating a neurokinin-1 receptor associated condition, comprising administering to a subject that has the condition an effective amount of the pharmaceutical composition of  claim 35 . 
     
     
         43 . The method of  claim 42 , wherein the condition is chronic pain. 
     
     
         44 . The method of  claim 42 , wherein the condition is posttraumatic stress disorder (PTSD). 
     
     
         45 . The method of  claim 42 , wherein the condition is itch.