Stable peptide-based furin inhibitors

Abstract

It is provided furin inhibitors and their uses for treating pathogen infection. Particularly, it is provided a method or use for the treatment of a pathogen infection, in a subject, comprising administering to the subject a therapeutically effective amount of the furin inhibitors or the composition disclosed, thereby preventing or treating pathogen infection, in the subject.

1 . A peptide sequence comprising the following formula I
   Z-Xaa 8 -Xaa 7 -Xaa 6 -Xaa 5 -Arg 4 -Xaa 3 -Xaa 2 -Arg 1 -Xaa 1′   (I)
   
       wherein
 Xaa 1′  is absent or any amino acids, peptidomimetic, or stereoisomer thereof; 
 Arg 1  and Arg 4  are independently arginine, an analogue of arginine or stereoisomer thereof; 
 Xaa 2  is a basic amino acid, an analogue or stereoisomer thereof; 
 Xaa 3  is independently any amino acids, an analogue or stereoisomer thereof; 
 Xaa 5 , Xaa 6 , Xaa 7  and Xaa 8  independently are Lys, Arg or His, peptidomimetic or stereoisomer thereof; and 
 Z comprises at least one of acetyl, azido and PEG group, fatty acids, steroid derivatives and sugars linked to the N-terminal of the peptide sequence; 
 
       with the proviso that Xaa 5 , Xaa 6 , Xaa 7  and Xaa 8  are not aromatic or negatively charged amino acids. 
     
     
         2 . The peptide sequence of  claim 1  wherein Xaa 2  is Lys, Arg or stereoisomer thereof and Xaa 3  is independently Lys, Val or stereoisomer thereof. 
     
     
         3 . The peptide sequence of  claim 1 , wherein at least one of Xaa 1′ , Arg 1 , Arg 4 , Xaa 5 , Xaa 6 , Xaa 7 , and Xaa 8  is an analogue of Lys or Arg. 
     
     
         4 . The peptide sequence of  claim 1 , wherein the analogue of arginine is represented by the following formula (III) 
       
         
           
           
               
               
           
         
       
       wherein
 W 1  is -alkyl-, -alkenylene-, -arylene-, -heteroarylene-, -arylalkylene-, -arylalkenylene-, —NR1-alkylene-, —NR1-alkenylene-, —NR1-arylene-, —NR1-heteroarylene-, —NR1-arylalkylene-, —NR1-arylalkenylene-, -alkylene-NR2-, -alkenylene-NR2-, -arylene-NR2-, -heteroarylene-NR2-, -arylalkylene-NR2-, -arylalkenylene-NR2-, —NR1 alkylene-NR2-, —NR1-alkenylene-NR2-, —NR1-arylene-NR2-, —NR1-heteroarylene-NR2-, —NR1-arylalkylene-NR2-, or —NR1-arylalkenylene-NR2-; each of which may be optionally substituted with at least of one substituent selected from alkyl, alkenyl, aryl, heteroaryl, alkylene-COOH, alkenylene-COOH, arylene-COOH, heteroarylene-COOH, arylalkylene-COOH, and heteroarylalkylene-COOH; and 
 R1 and R2 are independently H, alkyl, alkenyl, alkylene-COOH, alkenylene-COOH, arylene-COOH, heteroarylene-COOH, arylalkylene-COOH, heteroarylalkylene-COOH or alkenylcarboxy. 
 
     
     
         5 . The peptide sequence of  claim 4 , wherein W 1  is -arylalkylene-, -arylalkenylene-, —NR1-alkylene-, —NR1-alkenylene-, —NR1-arylene-, —NR1-arylalkylene-, -alkylene-NR2-, -alkenylene-NR2-, —NR1-alkenylene-NR2-, —NR1-arylene-NR2-, or —NR1-arylalkylene-NR2-. 
     
     
         6 . The peptide sequence of  claim 4 , wherein the analogue of arginine is represented by 
       
         
           
           
               
               
           
         
       
     
     
         7 . The peptide sequence of  claim 1 , wherein the analogue of Lys is represented by the following formula IV 
       
         
           
           
               
               
           
         
       
       wherein
 Y2 is N or CH; 
 R10 is H, alkyl, alkenyl or alkyl-NR11-R12; 
 R11 and R12 are independently H or alkyl; 
 W 2  is a bond, -alkylene-, -alkenylene-, -arylene-, -heteroarylene-, -arylalkylene-, -heteroarylalkylene-, -alkylarylene-, -alkylheteroarylene-, -alkenylarylene-, -alkenylheteroarylene-, each of which may be optionally substituted with at least of one substituent selected from alkyl, and alkenyl. 
 
     
     
         8 . The peptide sequence of  claim 7 , wherein W 2  is a bond, -alkylene-, -alkenylene-, -heteroarylene-, -arylalkylene-, -heteroarylalkylene-, -alkylarylene-, or -alkylheteroarylene-, each of which may be optionally substituted with at least of one substituent selected from alkyl, and alkenyl. 
     
     
         9 . The peptide of  claim 7 , wherein the analogue of Lys is represented by 
       
         
           
           
               
               
           
         
       
     
     
         10 . A composition comprising the peptide of  claim 1  and a carrier. 
     
     
         11 .- 16 . (canceled) 
     
     
         17 . A method of reducing pathogen proliferation or treating a pathogen infection in a subject, comprising administering the peptide of  claim 1  or the composition of  claim 10  to the subject, thereby reducing the proliferation of the pathogen in the subject or treating the pathogen infection in the subject. 
     
     
         18 . The method of  claim 17 , wherein the pathogen is Anthrax,  Pseudomonas , Botulism, Diphtheria,  Aeromonas, Shigella , Influenzavirus A, parainfluenza, Sindbis virus, Newcastle disease virus, flavivirus, cytomegalovirus, herpesvirus, HIV, Measles virus, infectious bronchitis virus, Coronavirus, Marburg virus, Ebola virus or Epstein-Barr virus. 
     
     
         19 .- 27 . (canceled) 
     
     
         28 . The method of  claim 17 , further comprising administering at least one anti-viral drug. 
     
     
         29 . The method of  claim 17 , wherein said peptide or composition is administered concurrently with at least one anti-viral drug. 
     
     
         30 . The method of  claim 17 , wherein said peptide or composition is administered by one of the following routes: oral, mucosal, intranasal, intraocular, intratracheal, intrabronchial, intrapleural, intraperitoneal, intracranial, intramuscular, intravenous, intraarterial, intralymphatic, subcutaneous, intratumoral, gastric, enteral, colonic, rectal, urethral or intravesical.