Cyclic NTCP-targeting peptides and their uses as entry inhibitors

Patent metadata

Field	Value
Publication number	US-11401304-B2
Application number	US-201615780129-A
Country	US
Kind code	B2
Filing date	Dec 15, 2016
Priority date	Dec 16, 2015
Publication date	Aug 2, 2022
Grant date	Aug 2, 2022

Abstract

The present invention relates to cyclic NTCP targeting peptides which are preS-derived peptides of hepatitis B virus (HBV). The present invention further relates to pharmaceutical compositions comprising at least one cyclic peptide. The present invention further relates to medical uses of said cyclic peptides and the pharmaceutical compositions, such as in the diagnosis, prevention and/or treatment of a liver disease or condition, and/or in the inhibition of HBV and/or HDV infection. The present invention further relates to methods of diagnosis, prevention and/or treatment of a liver disease or condition and/or the inhibition of HBV and/or HDV infection.

First claim

The invention claimed is:

1. A peptide comprising the amino acid sequence selected from

(SEQ. ID NO: 9)

cyclo[PNPLGFFPDH]

(SEQ. ID NO: 12)

cyclo[NPLGFFPDH]

(SEQ. ID NO: 15)

cyclo[PNPLGFFPDH]

(SEQ. ID NO: 28)

cyclo[PNPLGFLPD]

(SEQ. ID NO: 29)

cyclo[NPLGFLPDH]

(SEQ. ID NO: 30)

cyclo[PNPLGFLPDH]

(SEQ. ID NO: 31)

cyclo[GTNLSVPNPLGFLPDHQLDP],

wherein the peptide carries at least one hydrophobic modification, which an acylation with a C8 to C22 fatty acid and/or addition of hydrophobic moieties, or a pharmaceutically acceptable salt thereof.

2. The peptide of claim 1 , wherein the peptide is cyclized
(a) via thiol oxidation of two cysteines in the peptide,
(b) amide condensation of two amino acid side chains,
(c) via head-to-tail cyclization,
(d) via backbone cyclization,
(e) via thioether formation,
and/or
(f) via hydrogen bond formation and/or bond-forming derivatives of amino acids.

3. The peptide of claim 1 , further comprising an accessory domain, which is part of the cyclic peptide or is acyclic.

4. The peptide of claim 1 , wherein the peptide consists of the amino acid sequence selected from:

HBVpreS9-16
NPLGFFPD
(SEQ ID NO: 6)

HBVpreS8-16
PNPLGFFPD
(SEQ ID NO: 9)

HBVpreS9-1
NPLGFFPDH
(SEQ ID NO: 12)

HBVpreS8-17
PNPLGFFPDH
(SEQ ID NO: 15).

5. The peptide of claim 1 , comprising one or more further moieties,
selected from
drugs and their respective prodrugs;
tags;
labels;
recombinant viruses and derivatives thereof;
carrier or depots for drugs, prodrugs or labels;
immunogenic epitopes;
hormones;
inhibitors; and
toxins.

6. A pharmaceutical composition comprising:
(i) at least one peptide of claim 1 , and
(ii) optionally, a pharmaceutically acceptable carrier and/or excipient.

7. The peptide, according to claim 1 , wherein the peptide consists of the amino acid sequence selected from

(SEQ. ID NO: 9)

Myr-cyclo (myr-cyclo[PNPLGFFPD])

(SEQ. ID NO: 12)

Myr-cyclo (myr-cyclo[NPLGFFPDH])

and

(SEQ. ID NO: 15)

Myr-cyclo (myr-cyclo[PNPLGFFPDH]).

8. The peptide, according to claim 1 , wherein the peptide consists of the amino acid sequence selected from

(SEQ. ID NO: 9)

cyclo[PNPLGFFPD]

(SEQ. ID NO: 12)

cyclo[NPLGFFPDH]

(SEQ. ID NO: 15)

cyclo[PNPLGFFPDH]

(SEQ ID NO. 28)

cyclo[PNPLGFLPD]

(SEQ ID NO. 29)

cyclo[NPLGFLPDH]

(SEQ ID NO. 30)

cyclo[PNPLGFLPDH]

and

(SEQ ID NO. 31)

cyclo[GTNLSVPNPLGFLPDHQLDP].

Assignees

• Univ Heidelberg Ruprecht Karls

Inventors

• Urban Stephan
• Ni Yi
• Mier Walter

Classifications

• A61K49/0056 Primary

  Peptides, proteins, polyamino acids · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K7/64

  Cyclic peptides containing only normal peptide links · CPC title

• C07K7/50

  Cyclic peptides containing at least one abnormal peptide link · CPC title

• A61K51/088

  conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10) · CPC title