Synthetic N-acetyl-muramic acid derivatives and uses thereof

Patent metadata

Field	Value
Publication number	US-10988508-B2
Application number	US-201615568559-A
Country	US
Kind code	B2
Filing date	Apr 22, 2016
Priority date	Apr 24, 2015
Publication date	Apr 27, 2021
Grant date	Apr 27, 2021

Abstract

The present invention provides N-acetyl-muramic acid (NAM) derivatives having Formula I, wherein Xa is selected from the group consisting of X1-X59, Ya is selected from the group consisting of H, monophosphate, uridine diphosphate and ethyl azide linker prepared from 2-azido-ethanol, and Za is selected from the group consisting of OH, an ethylene diamine coupled fluorophore, a peptide and a peptide with an ethylene diamine coupled fluorophore, wherein the peptide is selected from the group consisting of a monopeptide, a dipeptide, a tripeptide and a pentapeptide. Also provided are methods for synthesizing NAM derivatives and methods for modulating Nod2 in cells, modifying bacterial cell wall or modulating innate immune response by a subject to bacterial cells upon exposure to NAM derivatives.

First claim

What is claimed:

1. An N-acetyl-muramic acid (NAM) derivative having formula I:

wherein Xa is selected from the group consisting of X22-X52 and X54-X59 as defined in table 1,
wherein Ya is selected from the group consisting of H, monophosphate, uridine diphosphate and ethyl azide linker prepared from 2-azido-ethanol, and
wherein Za is selected from the group consisting of OH, an ethylene diamine coupled fluorophore, a peptide and a peptide with an ethylene diamine coupled fluorophore, wherein the peptide is selected from the group consisting of a monopeptide, a dipeptide, a tripeptide and a pentapeptide.

2. The NAM derivative of claim 1 , wherein Za is OH.

3. The NAM derivative of claim 1 , wherein Xa is selected from the group consisting of X22, X24-X25, X28, X30-X35, X44-X52 and X54-X59 as defined in table 1.

4. The NAM derivative of claim 1 , wherein Xa is selected from the group consisting of X25, X28, X30, X31, X45-X48 and X54-X55 as defined in table 1.

5. The NAM derivative of claim 1 , wherein Za is a peptide, and wherein the NAM derivative is selected from the group consisting of compounds E, F, H, J, L, M, O, P, R, S, AG, AH, AP, AQ, AS, AT, AV, or AW as defined in table 2.

6. The NAM derivative of claim 3 , wherein the NAM derivative is selected from the group consisting of compounds A, B, C, D, G, AH, AQ, AT, AW and BD as defined in table 2.

7. The NAM derivative of claim 1 , wherein the NAM derivative is compound B or C as defined in table 2, and wherein the NAM derivative is synthesized in vitro in the presence of P. putida recycling enzymes AmgK and MurU.

8. The NAM derivative of claim 1 , wherein Za is a peptide, and wherein the NAM derivative is synthesized in vitro from compound B or C as defined in table 2 in the presence of E. coli biosynthetic enzymes MurC, MurD, MurE, and MurF.

9. The NAM derivative of claim 1 , wherein the NAM derivative is selected from the group consisting of compounds A, C, D and BD as defined in table 2.

10. A method for modulating nucleotide-binding oligomerization domain-containing protein 2 (Nod2) in a cell, comprising exposing the cell with an effective amount of the NAM derivative of claim 1 .

11. The method of claim 10 , further comprising stabilizing the Nod2 in the cell.

12. The method of claim 10 , further comprising activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the cell.

13. A method for modifying the cell wall of a bacterial cell, comprising
(a) exposing the bacterial cell to an effective amount of the NAM derivative of claim 2 ,
(b) making a peptidoglycan from the NAM derivative from step (a) in the bacterial cell, and
(c) incorporating the peptidoglycan from step (b) into the cell wall of the bacterial cell, whereby the modified cell wall of the bacterial cell is obtained.

14. The method of claim 13 , wherein Xa is selected from the group consisting of X22, X24-X25, X28, X30-X35, X44-X52 and X54-X59 as defined in table 1.

15. The method of claim 13 , wherein Xa is selected from the group consisting of X25, X28, X30, X31, X45-X48, X54 and X55 as defined in table 1.

Assignees

• Grimes Catherine Leimkuhler
• Melnyk James E
• Demeester Kristen E
• Liang Hai
• Univ Delaware

Inventors

• Grimes Catherine Leimkuhler
• Melnyk James E
• Demeester Kristen E
• Liang Hai

Classifications

• C07H11/04

  Phosphates; Phosphites; Polyphosphates · CPC title

• C07K9/005 Primary

  containing within the molecule the substructure [IMAGE cpc-sch-C07K-1009.gif] with m, n > 0 and m+n > 0, A, B, D, E being heteroatoms; X being a bond or a chain, e.g. muramylpeptides · CPC title

• A61K2039/52

  Bacterial cells; Fungal cells; Protozoal cells · 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

• C07H15/04

  attached to an oxygen atom of the saccharide radical · CPC title