Lipopeptides for use in treating liver diseases and cardiovascular diseases

Patent metadata

Field	Value
Publication number	US-12370237-B2
Application number	US-202318330135-A
Country	US
Kind code	B2
Filing date	Jun 6, 2023
Priority date	Nov 12, 2012
Publication date	Jul 29, 2025
Grant date	Jul 29, 2025

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.

First claim

The invention claimed is:

1. A method for the prevention and/or treatment of a liver disease or condition comprising administering a therapeutically effective amount of a lipopeptide-based compound,
wherein said 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 phenylalanine or leucine;
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;
m+n>11;
R is a C-terminal modification of said hydrophobic modified peptide, and
o is 0 or at least 1;

wherein the peptide comprises
18 to 19 consecutive amino acids of the amino acid sequence with SEQ ID NO. 18, 19, or 20, or an amino acid sequence having at least 90% sequence identity to any of SEQ ID Nos. 18 to 20, and
an N-terminal hydrophobic modification by acylation with myristoyl (C14), palmitoyl (C16), or stearoyl (C18);

wherein said liver disease or condition is related to sodium taurocholate cotransporter polypeptide (NTCP)-mediated transport of compounds into hepatocytes, and 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.

2. 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.

3. The method of claim 1 , wherein the NCTP-mediated transport is decreased or blocked by the lipopeptide-based compound.

4. The method of claim 1 , wherein m=4 to 19 and/or n=0 to 78.

5. The method of claim 1 , 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.

6. The method of claim 1 , 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); and
hormone(s).

7. The method of claim 6 , wherein the further moiety or moieties are covalently attached via a linker, spacer and/or an anchor group.

8. The method of claim 1 , wherein from 0.1 mg to 50 mg of the lipopeptide-based compound is administered per day.

9. The method of claim 1 , wherein the route of administration is selected from subcutaneous, intravenous, oral, nasal, intramuscular, transdermal, inhalative, and by suppository.

10. The method of claim 1 , wherein 1 mg to 20 mg of the lipopeptide-based compound is administered per day.

11. The method of claim 2 , wherein the compounds that are transported into hepatocytes via NTCP are cholate, taurocholate, glycocholate, taurodeoxycholate, taurochenodeoxycholate, tauroursodeoxycholate, estrone-3-sulfate, 17α-ethinylestradiol-3-O-sulfate, chlorambucil-taurocholate, an antifungal drug, an antihyperlipidemic drug, an antihypertensive drug, an anti-inflammatory drug, or glucocorticoid drugs.

12. The method of claim 11 , wherein the antifungal drug is micafungin and wherein the antihyperlipidemic drug is simvastatin, rosuvastatin, pitavastatin, fluvastatin, or atorvastatin).

Assignees

• Univ Heidelberg Ruprecht Karls
• Cleeves Volker

Inventors

• Cleeves Volker
• Urban Stephan
• Kubitz Ralf

Classifications

• G01N2500/10

  involving cells · CPC title

• G01N2500/04

  Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A) · CPC title

• G01N2333/705

  Assays involving receptors, cell surface antigens or cell surface determinants · CPC title

• G01N33/5023

  on expression patterns · CPC title

• C12N2730/10132

  Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent · CPC title