Antimicrobial peptides, variants and chemical analogues thereof and their uses

Patent metadata

Field	Value
Publication number	US-2025051403-A1
Application number	US-202218720105-A
Country	US
Kind code	A1
Filing date	Dec 16, 2022
Priority date	Dec 16, 2021
Publication date	Feb 13, 2025
Grant date	—

Abstract

The present invention relates to antimicrobial peptides, variants and chemical analogues thereof; in particular, a peptide of 20 amino acids, named Michelicin, having the sequence RVCVRICRNGRCYRRCWNT, derived from a longer precursor with a BRICHOS domain from the marine worm Capitella . The peptide has several cysteines which form disulfide bridges and provide stability in salt conditions. Several derivatives and analogues were produced. The peptide and the derivatives show antimicrobial activity against a wide range of bacteria. The application also concerns nucleic acid sequences encoding these, pharmaceutical composition and to their use as a drug, preservative and disinfectant.

First claim

1 .- 15 . (canceled)

16 . An isolated peptide, a variant or a chemical analogue thereof, wherein
(i) the isolated peptide and the variant thereof are selected from:
a) peptide consisting in any one of sequences selected from SEQ ID NO: 2 to SEQ ID NO: 11;
b) peptide comprising a sequence selected from any one of SEQ ID NO: 2 to SEQ ID NO: 11;
c) peptide as defined in a) or b) and comprising a modifying group of its C-terminal carboxyl group and/or of its N-terminal amine group;
d) peptide having at least 80% or at least 90% identity with peptide as defined in a), b) or c) and
e) retro and retro-inverso peptide of peptides as defined in a) to d),
(ii) the chemical analogues are selected from:
f) a chemical analogue consisting in any one of sequences selected from SEQ ID NO: 13 and SEQ ID NOs: 15 to 19;
g) a chemical analogue comprising a sequence selected from any one of SEQ ID NO: 13 and SEQ ID Nos: 15 to 19;
h) a chemical analogue as defined in f) or g) and comprising a modifying group of its C-terminal carboxyl group and/or of its N-terminal amine group,
i) a chemical analogue having at least 80% or at least 90% identity with analogues having sequences SEQ ID NO: 13 and SEQ ID NO: 16-19 as defined in f), g) or h) or having at least 90% identity with analogues having sequence SEQ ID NO: 15 as defined in f), g) or h);
j) retro and retro-inverso peptide of peptides as defined in f) to i),
said peptide and variants as defined in a) to e) and said chemical analogues as defined in f) to j) having an antimicrobial activity.

17 . The isolated peptide, variant or chemical analogue thereof of claim 16 , wherein
(i) the isolated peptide and the variant thereof are selected from:
d) peptide having at least 95% identity with peptide as defined in a), b) or c), and
(ii) the chemical analogues are selected from
i) a chemical analogue having at least 95% identity with analogues having sequences SEQ ID NO: 13 and SEQ ID NO: 16-19 as defined in f), g) or h) or having at least 95% identity with analogues having sequence SEQ ID NO: 15 as defined in f), g) or h).

18 . The isolated peptide, variants or chemical analogues thereof according to claim 16 , comprising at least two cysteines or four cysteines.

19 . The isolated peptide, variants or chemical analogues thereof according to claim 16 , wherein said peptide, variants or chemical analogues thereof is a L-peptide.

20 . The isolated peptide, variants or chemical analogues thereof according to claim 16 , wherein said peptide, variants or chemical analogues thereof is a non-folded peptide.

21 . The isolated peptide, variants or chemical analogues thereof according to claim 16 , wherein said N-terminal modifying group and/or said C-terminal modifying group are selected independently from each other from acetyl group; formyl group; palmitoyl group; fatty acids groups, myristoyl group, pyroglutamyl group; urea; 7-amino-4-methylcoumarinyl; carbamate; sulphonamide; alkylamine; benzoyl; benzyloxycarbonyl; dye; labels, biotin or fluorescent molecules; NH 2 ; —O-alkyl, particularly O-methyl, O-hexyl, O-decyl, O-tetradecanyl, O-methyl and O-ethyl; H; NHC 6 H 6 NO 2 (para); 7-amino-4-methylcoumarinyl; NHNH 2 ; NHOH; CH 2 Cl; (CH 2 ) 2 NH 2 ; NHCH 3 ; NHCH 2 CH 3 ; alkyl and methyl.

22 . The isolated peptide, variants or chemical analogues thereof according to claim 18 , wherein at least one of cysteines or all cysteines are replaced by an analogue of cysteine.

23 . The isolated peptide, variants or chemical analogues thereof according to claim 22 , wherein the analogue of cysteine is 2-aminobutanoic group.

24 . An isolated nucleic acid molecule encoding a peptide, variants or chemical analogues thereof of claim 16 , or a nucleic acid molecule encoding a peptide, variants or chemical analogues thereof of SEQ ID NO: 2 to SEQ ID NO: 11, 13 and 15 to 19.

25 . The isolated nucleic acid molecule of claim 24 which is a nucleic acid molecule of SEQ ID NO: 20.

26 . A recombinant nucleic acid construct comprising the nucleic acid molecule of claim 24 operably linked to an expression vector.

27 . A host cell comprising the recombinant nucleic acid construct of claim 26 .

28 . A pharmaceutical composition comprising:
at least one selected from: (i) the isolated peptide, variants or chemical analogues thereof according to claim 16 , (ii) an isolated nucleic acid molecule encoding the isolated peptide, variants or chemical analogues thereof according to claim 16 , (iii) a recombinant nucleic acid construct comprising the isolated nucleic acid molecule encoding the isolated peptide, variants or chemical analogues thereof according to claim 16 and an expression vector, and (iv) a host cell comprising a recombinant nucleic acid construct comprising the nucleic acid molecule encoding the isolated peptide, variants or chemical analogues thereof according to claim 16 and an expression vector; and a pharmaceutically acceptable excipient.

29 . A drug comprising
(i) the isolated peptide, variants or chemical analogues thereof according to claim 16 , (ii) an isolated nucleic acid molecule encoding the isolated peptide, variants or chemical analogues thereof according to claim 16 , (iii) a recombinant nucleic acid construct comprising the isolated nucleic acid molecule encoding the isolated peptide, variants or chemical analogues thereof according to claim 16 and an expression vector, (iv) a host cell comprising a recombinant nucleic acid construct comprising a nucleic acid molecule encoding the isolated peptide, variants or chemical analogues thereof according to claim 16 and an expression vector or (v) a pharmaceutical composition comprising at least one selected from: (i) said isolated peptide, variants or chemical analogues thereof (ii) said isolated nucleic acid molecule, (iii) said recombinant nucleic acid construct and (iv) said host cell and a pharmaceutically acceptable excipient.

30 . An antimicrobial agent comprising:
(i) the isolated peptide, variants or chemical analogues thereof according to claim 16 , (ii) an isolated nucleic acid molecule encoding the isolated peptide, variants or chemical analogues thereof according to claim 16 , (iii) a recombinant nucleic acid construct comprising the isolated nucleic acid molecule encoding the isolated peptide, variants or chemical analogues thereof according to claim 16 and an expression vector, (iv) a host cell comprising a recombinant nucleic acid construct comprising the nucleic acid molecule encoding the isolated peptide, variants or chemical analogues thereof according to claim 16 and an expression vector or (v) a pharmaceutical composition comprising at least one selected from: (i) said isolated peptide, variants or chemical analogues thereof (ii) said isolated nucleic acid molecule, (iii) said recombinant nucleic acid construct and (iv) said host cell and a pharmaceutically acceptable excipient.

31 . A method for treating an infection and/or disease caused by at least one bacterium selected from:
i) Gram negative bacteria selected from the group of genius consisting of: Acinetobacter, Salmonella, Escherichia, Pseudomonas, Klebsiella, Helicobacter, Vibrio, Burkholderia and Serratia; ii) Gram positive bacteria selected from the group of genius consisting of: Staphylococcus, Bacillus, Enterococcus and Clostridium , and iii) Mycobacterium species, comprising administrating to a subject in need thereof an anti-microbial agent according to claim 30 .

32 . The method of claim 31 , wherein:
i) in Gram neg

Assignees

• Univ Lille
• Centre Nat Rech Scient
• Univ Aix Marseille
• Univ Sorbonne
• Ecole Centrale Marseille

Inventors

• Tasiemski Aurélie
• Wichlacz Céline
• Maresca Marc
• Canaan Stéphane
• Cavalier Jean-François
• Mabrouk Kamel
• Hourdez Stéphane

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

• A61P31/04

  Antibacterial agents · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C07K14/43536 Primary

  from worms · CPC title