Antibacterial antisense oligonucleotide and method
View Patent ↗A method for enhancing, by at least 10 fold, the antibacterial activity of an antisense oligonucleotide composed of morpholino subunits linked by phosphorus-containing intersubunit linkages. The method includes one or both of: conjugating an arginine-rich carrier to a 3′ or 5′ end of the oligonucleotide and modifying the oligonucleotide to contain 20%-50% intersubunit linkages that are positively charged at physiological pH. Also disclosed is an antisense oligonucleotide having enhanced antibacterial activity by virtue of one or both modifications.
1. A compound having the following formula (I):
or a salt thereof, wherein:
R 1 is H or trityl;
R 2 is H or
and
R 3 is H or a linkage to a solid support.
2. The compound of claim 1 , wherein the compound has the following structure:
3. The compound of claim 1 , wherein R 2 is
4. The compound of claim 3 , wherein the compound has the following structure:
5. The compound of claim 3 , wherein the compound has the following structure:
wherein R 3 is a linkage to a solid support.
6. The compound of claim 3 , wherein the compound has the following structure:
wherein R 3 is a linkage to a solid support.
7. The compound of claim 1 , wherein the solid support comprises aminomethylpolystyrene.
8. An oligomer of 10 to 40 morpholino subunits connected by phosphorous-containing linkages of the formula:
wherein:
each X is at, each occurrence, independently alkyl, alkoxy, thioalkoxy, —NR 2 or 1-piperazinyl, wherein at least one of the X moieties in the oligomer is 1-piperazinyl;
each R is, at each occurrence, independently hydrogen or C 1 -C 6 alkyl; and
each B is, at each occurrence, independently a purine or pyrimidine base-pairing moiety selected from adenine, cytosine, guanine, uracil, thymine and inosine, wherein the 5′ terminal morpholino subunit comprises a group of the formula:
wherein:
each R is defined as above;
R 2 is H or
and
R 3 is H or a linkage to a solid support.
9. The oligomer of claim 8 , wherein each X that is not 1-piperazinyl is —NR 2 , wherein each R is methyl.
10. A solid support covalently bound to a compound having the following structure:
wherein:
R 1 is H or trityl; and
R 3 is a linkage to the solid support.
11. The solid support of claim 10 , wherein R 1 is H.
12. The solid support of claim 10 , wherein R 1 is trityl.
13. The solid support of claim 10 , wherein the solid support comprises aminomethylpolystyrene.
14. The oligomer of claim 8 , wherein the 5′ terminal morpholino subunit is of a formula:
15. The oligomer of claim 8 , wherein the oligomer is of a formula:
wherein:
X and B are as defined in claim 8 ;
Z is an integer from 4 to 19;
R 4 is selected from H, trityl and acetyl; and
R 5 is selected from an electron pair, C 1 -C 6 alkyl and H.
16. The oligomer of claim 15 , wherein each X that is not 1-piperazinyl is —NR 2 , wherein each R is methyl.
17. The oligomer of claim 15 , wherein each B is independently selected from adenine, cytosine, guanine, uracil and thymine.
18. A compound of formula:
or a pharmaceutically acceptable salt thereof, wherein:
Z is an integer from 3 to 19;
each X is, at each occurrence, independently alkyl, alkoxy, thioalkoxy, —NR 2 or 1-piperazinyl, wherein at least one of the X moieties in the oligomer is 1-piperazinyl;
each R is, at each occurrence, independently hydrogen or C 1 -C 6 alkyl; and
each B is independently a purine or pyrimidine base-pairing moiety selected from adenine, cytosine, guanine, uracil, thymine, and inosine.