Lipopeptides for Use in Treating Liver Diseases and Cardiovascular Diseases

Abstract

The present invention relates to lipopeptide-based compounds for use in the diagnosis, prevention and/or treatment of a liver disease or condition, preferably liver involved metabolic diseases, as well as in the control or modification of the cholesterol level or cholesterol uptake and, thus, diagnosis, prevention and/or treatment of a cardiovascular disease. The present invention furthermore relates to an in vitro or in vivo assay or method for testing or measuring the NTCP-mediated transport of test compound(s). The present invention furthermore relates to a method for the diagnosis, prevention and/or treatment of a liver disease or condition, comprising administering a therapeutically effective amount of a lipopeptide-based compound to a patient. The present invention furthermore relates to a method for the diagnosis, prevention and/or treatment of a cardiovascular disease.

1 . A method for the diagnosis, prevention and/or treatment of a liver disease or condition, wherein said liver disease or condition is related to sodium taurocholate cotransporter polypeptide (NTCP)-mediated transport of compounds into hepatocytes, wherein said method comprises utilizing a lipopeptide-based compound. 
     
     
         2 . The method of  claim 1 , wherein said liver disease or condition that is related to NTCP-mediated transport of compounds into hepatocytes, is a liver involved metabolic disease selected from:
 intrahepatic cholestasis,   poisoning of the liver (by liver toxins)/hepatotoxicity,   drug-induced cholestatic liver disease,   hyperlipidemia, and   posthepatic cholestasis.   
     
     
         3 . The method of  claim 1 , wherein the compounds that are transported into hepatocytes via NTCP are:
 bile acids,   taurine- or glycine conjugated bile acids and salts thereof,   taurine- or glycine conjugated dihydroxy and trihydroxy bile salts,   sulfated bile acids and salts thereof,
 steroids, 
 steroid sulfates, 
 estrogen conjugates, 
 dehydroepiandrosterone sulfate, 
 conjugated and non-conjugated thyroid hormones, 
 liver toxins, 
 compounds that are covalently bound to taurocholate, 
 bromosulphophthalein, or 
   drugs.   
     
     
         4 . The method of  claim 1 , wherein the NCTP-mediated transport is decreased or blocked by the lipopeptide-based compound. 
     
     
         5 . The method of  claim 1 , wherein the lipopeptide-based compound comprises a peptide of the general formula
   X—P—Y—R o  
   wherein   P is the amino acid sequence NPLGFXaaP (SEQ. ID NO: 1),
 wherein Xaa is an arbitrary amino acid; 
   X is an amino acid sequence having a length of m amino acids,
 wherein m is at least 4; 
   Y is an amino sequence having a length of n amino acids,
 wherein n is 0 or at least 1; 
   and wherein m+n>11;   R is a C-terminal modification of said hydrophobic modified peptide, and   o is 0 or at least 1.   
     
     
         6 . The method of  claim 5 , wherein m=4 to 19 and/or n=0 to 78. 
     
     
         7 . The method of  claim 5 , wherein the peptide comprises 18 to 119 consecutive amino acids of the amino acid sequences of SEQ ID NOs: 2 to 14 or variants thereof. 
     
     
         8 . The method of  claim 5 , wherein the peptide comprises one or more hydrophobic modification(s) at an amino acid side chain, wherein the hydrophobic modification is an acylation and/or addition of one or more hydrophobic moieties. 
     
     
         9 . The method of  claim 5 , wherein the lipopeptide is Myrcludex B having the amino acid sequence of SEQ ID NO. 18 with an N-terminal myristoylation and a C-terminal amide. 
     
     
         10 . The method of  claim 5 , comprising a further moiety or moieties, selected from drug(s) or their respective prodrug(s);
 tag(s);   label(s);   recombinant virus(s) or derivative(s) thereof;   carrier or depot(s) for drug(s), prodrug(s) or label(s);   immunogenic epitope(s);   hormone(s); and   compounds that are transported into hepatocytes via NTCP selected from:   bile acids;   taurine- or glycine conjugated bile acids and salts thereof;   taurine- or glycine conjugated dihydroxy and trihydroxy bile salts;   sulfated bile acids and salts thereof;   steroids;   steroid sulfates;   estrogen conjugates;   dehydroepiandrosterone sulfate;   conjugated and non-conjugated thyroid hormones;   liver toxins;   compounds that are covalently bound to taurocholate;   bromosulphophthalein; and   drugs.   
     
     
         11 . The method of  claim 10 , wherein the further moiety or moieties are covalently attached via a linker, spacer and/or an anchor group. 
     
     
         12 . The method of  claim 1 , wherein the lipopeptide-based compound is administered in a therapeutically effective amount. 
     
     
         13 . A method for the diagnosis, prevention and/or treatment of a cardiovascular disease (CVD), comprising the use of a lipopeptide-based compound. 
     
     
         14 . The method of  claim 13 , comprising control or modification of cholesterol level or cholesterol uptake,
 wherein the cholesterol level or uptake is controlled or modified by decreasing or blocking the NCTP-mediated bile salt transport by the lipopeptide-based compound.   
     
     
         15 . An in vitro or in vivo assay or method for testing or measuring the NTCP-mediated transport of test compound(s), comprising the steps of
 (a) providing test compound(s) and a lipopeptide-based compound as defined in  claim 5 ;   (b) providing a test system for functional and selective NTCP expression;   (c) adding the test compound(s), either together with or without the lipopeptide-based compound, to the NTCP test system of (b); and   (d) determining whether the test compound(s) are transported via NTCP by comparing the results of step (b) and (c) each with or without the addition of the lipopeptide-based compound,   wherein a test compound is considered being transported via NTCP when the compound(s) decrease, block or inhibit bile salt transport by NTCP (competitive transport) or when the transport of the compound(s) can be decreased, blocked or inhibited by the addition of the lipopeptide-based compound.   
     
     
         16 . The method of  claim 1 , wherein the therapeutically effective amount of the lipopeptide-based compound is in the range of from about 0.1 mg to about 50 mg per patient and per day. 
     
     
         17 . The method according to  claim 13 ,
 comprising administering a therapeutically effective amount of a lipopeptide-based compound to a patient, wherein the lipopeptide-based compound comprises a peptide of the general formula
   X—P—Y—R o  
 
   wherein   P is the amino acid sequence NPLGFXaaP (SEQ. ID NO: 1),
 wherein Xaa is an arbitrary amino acid; 
   X is an amino acid sequence having a length of m amino acids,
 wherein m is at least 4; 
   Y is an amino sequence having a length of n amino acids,
 wherein n is 0 or at least 1; 
   and wherein m+n>11;   R is a C-terminal modification of said hydrophobic modified peptide, and   o is 0 or at least 1.   
     
     
         18 . The method of  claim 1 , wherein the route of administration is selected from subcutaneous, intravenous, oral, nasal, intramuscular, transdermal, inhalative, and by suppository. 
     
     
         19 . The method, according to  claim 7 , wherein the peptide comprises a variant having an amino acid sequence selected from:
 SEQ ID NO. 18 HBV preS/2-48 (genotype C),   SEQ ID NO. 19 HBV preS/2-48 (genotype D),   SEQ ID NO. 20 HBV preS/2-48 (consensus), and   amino acid sequences having at least 90% sequence identity to any of SEQ ID NOs. 18 to 20.   
     
     
         20 . The method of  claim 13 , wherein the route of administration is selected from subcutaneous, intravenous, oral, nasal, intramuscular, transdermal, inhalative, and by suppository.