Labyrinthopeptins as anti-viral agents

Abstract

The present invention relates to novel labyrinthopeptin derivatives. These labyrinthopeptin derivatives are useful for the treatment of infectious diseases, such as an infectious disease caused by an infection with human respiratory syncytial virus (RSV), Kaposi sarcoma-associated herpesvirus (KSHV), cytomegalovirus (CMV/HCMV), dengue virus (DENV), chikungunya virus (CHIKV), tick-borne encephalitis virus (TBEV; FSME virus), vesicular stomatitis Indiana virus (VSV), zika virus (ZIKV) and/or hepatitis C virus (HCV). Said labyrinthopeptin derivatives are also useful for analyzing the mode of action of labyrinthopeptins. Also encompassed by the present invention are labyrinthopeptins for use in treating an infectious disease, in particular an infectious disease caused by an infection with any one of the viruses selected from RSV, KSHV, CMV, CHIKV, TBEV, VSV, ZIKV and HCV. The invention further relates to a combination of labyrinthopeptin A1 and A2 for use as a medicament, e.g. for treating an infectious disease caused by an infection with RSV, KSHV, CMV, DENV, CHIKV, TBEV, VSV, ZIKV and/or HCV.

1 . A peptide comprising the amino acid sequence 
       
         
           
           
               
               
           
         
         wherein 
         Lab is labionin 
         X 1  is an amino acid selected from Asn, Asp, and Glu; 
         X 2  is an amino acid selected form Ala, Trp, and Ser; 
         X 3  is an amino acid selected from Val, Leu, and Ile; 
         X 4  is an amino acid selected from Trp and Tyr; 
         X 5  is an amino acid selected from Glu and Asp; 
         X 6  is an amino acid selected from Thr and Ser; 
         X 7  is an amino acid selected from Gly and Pro; 
         X 8  consists of a sequence of 3 to 5 amino acids; 
         R 1  is selected from H, a (C 2 -C 12 )alkynyl, a C(O)—(C 2 -C 12 )alkynyl, a C(O)—O—(C 2 -C 12 )alkynyl, and a C(O)NH—(C 2 -C 12 )alkynyl; wherein R 1  carries the alkynyl group at the terminal position, and 
         R 2  is selected from H, a [C(O)]—NH—(C 2 -C 12 )alkynyl or a [C(O)]—O—(C 2 -C 12 )alkynyl; wherein the moiety [C(O)] is the carbonyl group of the terminal amino acid; wherein R 2  carries the alkynyl group at the terminal position;
 wherein if R 1  is H, then R 2  is not H. 
 
       
     
     
         2 . The peptide of  claim 1 , wherein R 1  and/or R 2  is/are derivatized with an azide-labeled compound. 
     
     
         3 . The peptide of  claim 2 , wherein said compound is a compound selected from an anti-viral drug or a marker molecule. 
     
     
         4 . (canceled) 
     
     
         5 . A pharmaceutical composition comprising the peptide of  claim 1 , and a pharmaceutically acceptable carrier and/or diluent. 
     
     
         6 . A method of treating and/or preventing an infection in a subject, wherein the method comprises administering an effective dose of the peptide of  claim 1 . 
     
     
         7 . The method of  claim 6 , wherein said infection is an infection with any one of the viruses selected from human respiratory syncytial virus (RSV), Kaposi sarcoma-associated herpesvirus (KSHV), cytomegalovirus (CMV), dengue virus (DENV), chikungunya virus (CHIKV), tick-borne encephalitis virus (TBEV; FSME virus), vesicular stomatitis Indiana virus (VSV) zika virus (ZIKV) and hepatitis C virus (HCV). 
     
     
         8 . The method of  claim 11 , wherein said infection is an infection with any one of the viruses selected from RSV, KSHV, CMV, DENV, CHIKV, TBEV, VSV, ZIKV and HCV. 
     
     
         9 . A peptide comprising the amino acid sequence 
       
         
           
           
               
               
           
         
         wherein 
         Lab is labionin 
         X 1  is an amino acid selected from Asn, Asp, and Glu; 
         X 2  is an amino acid selected form Ala, Trp, and Ser; 
         X 3  is an amino acid selected from Val, Leu, and Ile; 
         X 4  is an amino acid selected from Trp and Tyr; 
         X 5  is an amino acid selected from Glu and Asp; 
         X 6  is an amino acid selected from Thr and Ser; 
         X 7  is an amino acid selected from Gly and Pro; and 
         X 8  consists of a sequence of 3 to 5 amino acids. 
       
     
     
         10 . A pharmaceutical composition comprising the peptide of  claim 9 , and a pharmaceutically acceptable carrier and/or diluent. 
     
     
         11 . A method of treating and/or preventing an infection in a subject, wherein the method comprises administering an effective dose of the peptide as defined in  claim 9  to a subject in need of such a treatment. 
     
     
         12 . The peptide of  claim 1 , wherein said peptide has a length of maximal 30 amino acids. 
     
     
         13 . The peptide of  claim 1 , wherein
 X 1  is Asn or Asp;   X 2  is Ala or Trp;   X 3  is Val or Leu;   X 4  is Trp;   X 5  is Glu;   X 6  is Thr;   X 7  is Gly; and   X 8  is an amino acid sequence consisting of the amino acid sequence Trp-Val-Pro-Phe-dehydrobutyrine, the amino acid sequence Leu-Phe-Ala.   
     
     
         14 . The peptide of  claim 1 , wherein
 X 1  is Asn;   X 2  is Ala;   X 3  is Val;   X 4  is Trp;   X 5  is Glu;   X 6  is Thr;   X 7  is Gly; and   X 8  is an amino acid sequence consisting of the amino acid sequence Trp-Val-Pro-Phe-dehydrobutyrine.   
     
     
         15 . The peptide of  claim 1 , wherein
 X 1  is Asp;   X 2  is Trp;   X 3  is Leu;   X 4  is Trp;   X 5  is Glu;   X 6  is Thr;   X 7  is Gly; and   X 8  is an amino acid sequence consisting of the amino acid sequence Leu-Phe-Ala.   
     
     
         16 . A composition comprising the peptide as defined in  claim 14  and the peptide as defined in  claim 15 . 
     
     
         17 . The composition as defined in  claim 16 , wherein the composition further comprises a pharmaceutically acceptable carrier and/or diluent. 
     
     
         18 . A method of treating and/or preventing an infection in a subject, wherein the method comprises administering an effective dose of the pharmaceutical composition as defined in  claim 17  to a subject in need thereof. 
     
     
         19 . The method of  claim 18 , wherein the infection is an infection with any one of the viruses selected from RSV, KSHV, CMV, DENV, CHIKV, TBEV, VSV, ZIKV and HCV. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 6 , wherein the method further comprises co-administration with at least one other active agent. 
     
     
         22 . The method of  claim 21 , wherein the other active agent is a CMV inhibitor, a KSHV inhibitor, a RSV inhibitor, a DENV inhibitor, a CHIKV inhibitor, a TBEV inhibitor, a VSV inhibitor, a ZIKV inhibitor, or a HCV inhibitor. 
     
     
         23 . The method of  claim 6 , wherein the peptide is administered orally, intravenously, subcutaneously or intramuscularly. 
     
     
         24 . The method of claim, wherein the virus is CMV. 
     
     
         25 . The method of  claim 8 , wherein the virus is DENV.