Antimicrobial peptides and methods of use

Patent metadata

Field	Value
Publication number	US-11643438-B2
Application number	US-201917260148-A
Country	US
Kind code	B2
Filing date	Jul 19, 2019
Priority date	Jul 20, 2018
Publication date	May 9, 2023
Grant date	May 9, 2023

Abstract

Cyclic depsipeptide-class molecules, referred to herein as persephacins (including analogs thereof), having similarities to aureobasidin A, are described. The persephacins have antimicrobial activity, such as antifungal activity against a diverse range of clinically-relevant fungal pathogens, antiprotozoan parasite activity, and antibacterial activity, and can be used for example in treatments of difficult-to-treat ocular fungal infections at lower concentrations than natamycin. The active compounds may be combined with a secondary compound in a composition.

First claim

What is claimed is:

1. A method of treating a fungal infection in a subject in need of such treatment, wherein the method comprises:
administering to the subject a compound comprising Formula II or a stereoisomer thereof:

wherein:
X 1 is NH;
X 2 is NH;
X 3 is NH;
X 4 is O;
R 1 is selected from the group consisting of a side chain of persaphanine and structural and optical isomers thereof, wherein persephanine has the structure:

R 2 is selected from the group consisting of hydrogen (H), deuterium (D), methyl, ethyl, linear or branched C 3 -C 20 alkyl, a side chain of amino acid, a linear or branched C 3 -C 20 alkenyl, and a linear or branched C 2 -C 20 alkynyl;
R 3 is selected from the group consisting of alkyl or branched C 1 -C 6 alkyl, C 1 -C 6 alkyl ether, and C 1 -C 6 alkyl amine;
R 4 , R 5 , R 6 , R 8 , R 9 are independently selected from the group consisting of straight chain or branched C 1 -C 5 alkyl, straight chain or branched C 1 -C 5 alkenyl, straight chain or branched C 1 -C 5 alkynyl, straight chain or branched C 1 -C 5 alkyl halide, straight chain or branched C 1 -C 5 alkenyl halide, straight chain or branched C 1 -C 5 alkynyl halide, straight chain or branched C 1 -C 5 alkyl amine, straight chain or branched C 1 -C 5 alkenyl amine, straight chain or branched C 1 -C 5 alkynyl amine, straight chain or branched C 1 -C 5 alkyl alcohol, straight chain or branched C 1 -C 5 alkenyl alcohol, straight chain or branched C 1 -C 5 alkynyl alcohol, straight chain or branched C 1 -C 5 alkyl ether, straight chain or branched C 1 -C 5 alkenyl ether, straight chain or branched C 1 -C 5 alkynyl ether, straight chain or branched C 1 -C 5 alkyl thiol, straight chain or branched C 1 -C 5 alkenyl thiol, straight chain or branched C 1 -C 5 alkynyl thiol, straight chain or branched C 1 -C 5 alkyl sulfide, straight chain or branched C 1 -C 5 alkenyl sulfide, straight chain or branched C 1 -C 5 alkynyl sulfide, straight chain or branched C 1 -C 5 alkyl sulfoxide, straight chain or branched C 1 -C 5 alkenyl sulfoxide, straight chain or branched C 1 -C 5 alkynyl sulfoxide, straight chain or branched C 1 -C 5 alkyl sulfone, straight chain or branched C 1 -C 5 alkenyl sulfone, straight chain or branched C 1 -C 5 alkynyl sulfone, straight chain or branched C 1 -C 5 alkyl nitrile, straight chain or branched C 1 -C 5 alkenyl nitrile, straight chain or branched C 1 -C 5 alkynyl nitrile, straight chain or branched C 1 -C 5 alkyl isonitrile, straight chain or branched C 1 -C 5 alkenyl isonitrile, straight chain or branched C 1 -C 5 alkynyl isonitrile, straight chain or branched C 1 -C 5 alkyl nitrite, straight chain or branched C 1 -C 5 alkenyl nitrite, straight chain or branched C 1 -C 5 alkynyl nitrite, straight chain or branched C 1 -C 5 alkyl oxime, straight chain or branched C 1 -C 5 alkenyl oxime, straight chain or branched C 1 -C 5 alkynyl oxime, straight chain or branched C 1 -C 5 alkyl nitroso, straight chain or branched C 1 -C 5 alkenyl nitroso, straight chain or branched C 1 -C 5 alkynyl nitroso, straight chain or branched C 1 -C 5 alkyl nitro, straight chain or branched C 1 -C 5 alkenyl nitro, straight chain or branched C 1 -C 5 alkynyl nitro, straight chain or branched C 1 -C 5 alkyl nitrate, straight chain or branched C 1 -C 5 alkenyl nitrate, straight chain or branched C 1 -C 5 alkynyl nitrate, straight chain or branched C 1 -C 5 alkyl imide, straight chain or branched C 1 -C 5 alkenyl imide, straight chain or branched C 1 -C 5 alkynyl imide, straight chain or branched C 1 -C 5 alkyl imine, straight chain or branched C 1 -C 5 alkenyl imine, straight chain or branched C 1 -C 5 alkynyl imine, straight chain or branched C 1 -C 5 alkyl amide, straight chain or branched C 1 -C 5 alkenyl amide, straight chain or branched C 1 -C 5 alkynyl amide, straight chain or branched C 1 -C 5 alkyl ester, straight chain or branched C 1 -C 5 alkenyl ester, straight chain or branched C 1 -C 5 alkynyl ester, straight chain or branched C 1 -C 5 alkyl ketone, straight chain or branched C 1 -C 5 alkenyl ketone, straight chain or branched C 1 -C 5 alkynyl ketone, straight chain or branched C 1 -C 5 alkyl carbonate, straight chain or branched C 1 -C 5 alkenyl carbonate, straight chain or branched C 1 -C 5 alkynyl carbonate, straight chain or branched C 1 -C 5 (cyclopropyl)alkyl, straight chain or branched C 1 -C 5 (cyclopropyl)alkenyl, straight chain or branched C 1 -C 5 (cyclopropyl)alkynyl, straight chain or branched C 1 -C 5 (cyclobutyl)alkyl, straight chain or branched C 1 -C 5 (cyclobutyl)alkenyl, straight chain or branched C 1 -C 5 (cyclobutyl)alkynyl, straight chain or branched C 1 -C 5 alkyl silane, straight chain or branched C 1 -C 5 alkenyl silane, straight chain or branched C 1 -C 5 alkynyl silane, straight chain or branched C 1 -C 5 alkyl, straight chain or branched C 1 -C 5 alkynyl, methyl, ethyl, propyl, butyl, methyl imidazole, butyl amine, propyl guanidine, methyl-1-ol, ethyl-2-ol, ethyl-1-ol, ethyloic acid, propanoic acid, carboxymethyl, carboxyethyl, ethylamide, propylamide, methyl-1-thiol, ethyl-1-thiol, methyl sulfane, ethyl sulfane, isobutyl, sec-butyl, Cert-butyl, and isopropyl;
R 7 is selected from the group consisting of straight chain or branched C 1 -C 5 alkyl alcohol, straight chain or branched C 1 -C 5 alkenyl alcohol, straight chain or branched C 1 -C 5 alkynyl alcohol, straight chain or branched C 1 -C 5 alkyl amine, straight chain or branched C 1 -C 5 alkenyl amine, straight chain or branched C 1 -C 5 alkynyl amine, straight chain or branched C 1 -C 5 alkyl thiol, straight chain or branched C 1 -C 5 alkenyl thiol, and straight chain or branched C 1 -C 5 alkynyl thiol; and
R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are independently selected from the group consisting of H, D, linear or branched C 1 -C 5 alkyl, methyl, and ethyl.

2. The method of claim 1 , wherein the fungal infection is an ocular fungal infection and the compound is topically administered.

3. The method of claim 1 , wherein the compound comprising Formula II is:

Assignees

• Univ Oklahoma

Inventors

• Cichewicz Robert H
• Du Lin
• You Jianlan
• Mattes Allison O
• Srivastava Shikha
• Haldar Saikat

Classifications

• 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

• C07K11/02 Primary

  cyclic, e.g. valinomycins {; Derivatives thereof} · CPC title

• A61K45/06 Primary

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P31/10

  Antimycotics · CPC title