Antisense antibacterial compounds and methods

Patent metadata

Field	Value
Publication number	US-12209240-B2
Application number	US-202117498880-A
Country	US
Kind code	B2
Filing date	Oct 12, 2021
Priority date	Dec 23, 2015
Publication date	Jan 28, 2025
Grant date	Jan 28, 2025

Abstract

Provided are antisense oligomers targeted against bacterial mRNAs and other macromolecules associated with a biochemical pathway and/or cellular process, and related compositions and methods of using the oligomers and compositions to treat an infected mammalian subject, for example, as primary antimicrobials or as adjunctive therapies with classic antimicrobials.

First claim

The invention claimed is:

1. An antisense morpholino oligomer of formula (I):

or a pharmaceutically acceptable salt thereof,

where each Nu is a nucleobase which taken together forms a targeting sequence, where the targeting sequence is SEQ ID NO: 1 (CTC ATACCTTG);
and where thymine bases (T) may be uracil bases (U)
X is an integer from 9 to 38;
T is selected from OH and a moiety of the formula:

where each R 4 is independently C1-C6 alkyl, and R 5 is selected from an electron pair and H, and R 6 is selected from OH, —N(R 7 )CH 2 C(O)NH 2 , and a moiety of the formula:

where:
R 7 is selected from H and C 1 -C 6 alkyl, and
R 8 is selected from G, —C(O)—R 9 OH, acyl, trityl, and 4-methoxytrityl, where:
R 9 is of the formula —(O-alkyl) y - where y is an integer from 3 to 10 and each of the y alkyl groups is independently selected from C 2 -C 6 alkyl;
each instance of R 1 is —N( 10 ) 2 R 11 where each R 10 is independently C2-C6 alkyl, and R 11 is selected from an electron pair and H;
R 2 is selected from H, G, acyl, trityl, 4-methoxytrityl, benzoyl, stearoyl, and a moiety of the formula:

where L is selected from —C(O)(CH 2 ) 6 C(O)— and —C(O)(CH 2 ) 2 S 2 (CH 2 ) 2 C(O)— and each R 12 is of the formula —(CH 2 ) 2 OC(O)N(R 14 ) 2 where each R 14 is of the formula —(CH 2 ) 6 NHC(═NH)NH 2 ; and
R 3 is selected from an electron pair, H, and C1-C6 alkyl,
where G is a cell penetrating peptide (“CPP”) and linker moiety selected from —C(O)(CH 2 ) 5 NH—CPP, —C(O)(CH 2 ) 2 NH—CPP, —C(O)(CH 2 ) 2 N HC(O)(CH 2 ) 5 NH—CPP, and —C(O)CH 2 NH—CPP, or G is of the formula:

where the CPP is attached to the linker moiety by an amide bond at the CPP carboxy terminus, with the proviso that only one instance of G is present,
where the targeting sequence specifically hybridizes to a bacterial nRNA target sequence that encodes a protein associated with a biochemical pathway and/or cellular process, or a ribosomal RNA (rRNA) target sequence.

2. The antisense morpholino oligomer of claim 1 , where T is selected from:

3. The antisense morpholino oligomer of claim 1 , where R 2 is selected from H, G, acyl, trityl, 4-methoxytrityl, benzoyl, and stearoyl.

4. The antisense morpholino oligomer of claim 1 , where T is selected from:

R 2 is G.

5. The antisense morpholino oligomer of claim 1 , where T is of the formula:

R 6 is of the formula:

and R 2 is G.

6. The antisense morpholino oligomer of claim 1 , where T is of the formula:

and R 2 is G.

7. The antisense morpholino oligomer of claim 1 , where T is of the formula:

8. The antisense morpholino oligomer of claim 7 , where R 2 is selected from H, acyl, trityl 4-methoxytrityl, benzoyl, and stearoyl.

9. The antisense morpholino oligomer of claim 1 , where at least one instance of R 1 is —N(CH 3 ) 2 .

10. The antisense morpholino oligomer of claim 9 , where each R 1 is —N(CH 3 ) 2 .

11. The antisense morpholino oligomer of claim 1 , where the CPP is selected from:

where R a is H.

12. The antisense morpholino oligomer of claim 1 , where G is selected from:

where R a is H.

13. The antisense morpholino oligomer of claim 1 , where the antisense oligomer is of the formula (VII) selected from:

or a pharmaceutically acceptable salt of any of the foregoing,

where R a is H, and R b is selected from H, acetyl, benzoyl, stearoyl, trityl, and 4-methoxytrityl.

14. The antisense morpholino oligomer of claim 13 , where R a and R b are H.

15. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and an antisense morpholino oligomer according to claim 1 .

16. A method of reducing expression and activity of a protein associated with a biochemical pathway and/or cellular process in a bacterium, comprising contacting the bacterium with an antisense morpholino oligomer according to claim 1 .

Assignees

• Univ Texas
• Univ Oregon State

Inventors

• Greenberg David
• Geller Bruce L

Classifications

• A61K47/42

  Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein (oligopeptides having up to five amino acids {A61K47/183}; polyamino acids A61K47/34) · CPC title

• A61K31/712

  Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose · CPC title

• A61K31/7115

  Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine · CPC title

• A61K47/66

  the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells · CPC title

• C12N2310/3513

  Protein; Peptide · CPC title