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US 2019/0169609 A1Published application
Antisense antibacterial compounds and methods
AssigneesOregon State University, Board of Regents, The University of Texas System
InventorsBruce L. Geller, David Greenberg
Life of this patent
Estimating the term…
Abstract
Provided are antisense oligonucleotides targeted against bacterial genes involved in biochemical pathways and/or cellular processes, and related compositions and methods of using the oligonucleotides and compositions, alone or in combination with other antimicrobial agents, for instance, in the treatment of an infected mammalian subject.
Claims23
A compound of formula (I):
- or a pharmaceutically acceptable salt thereof, wherein:
- each Nu is a nucleobase which taken together forms a nucleobase sequence;
- Z is an integer from 8 to 38;
- T is selected from OH and a moiety of the formula:
- wherein:
- each R4 is independently C1-C6 alkyl, and
- R5 is selected from an electron pair and H, and
- R6 is selected from —N(R7)CH2C(O)NH2, and a moiety of the formula:
- wherein:
- R7 is selected from H and C1-C6 alkyl;
- and
- R8 is selected from G, —C(O)—R9, acyl, trityl, and 4-methoxytrityl,
- wherein:
- R9 is of the formula —(O-alkyl)y-OH wherein y is an integer from 3 to 10 and each of the y alkyl groups is independently selected from C2-C6 alkyl;
- each instance of R1 is —N(R10)2R11 wherein each R10 is independently C1-C6 alkyl, and R11 is selected from an electron pair and H;
- R2 is selected from the group consisting of H, G, acyl, trityl, 4-methoxytrityl, and a moiety of the formula:
- wherein,
- L is selected from —C(O)(CH2)6C(O)— and —C(O)(CH2)2S2(CH2)2C(O)—;
- and
- each R12 is of the formula —(CH2)2OC(O)N(R26)2 wherein each R26 is of the formula (CH2)6NHC(═NH)NH2;
- and
- R3 is selected from the group consisting of an electron pair, H, and C1-C6 alkyl,
- wherein G is a cell penetrating peptide (“CPP”) and linker moiety selected from the group consisting of —C(O)(CH2)5NH—CPP, —C(O)(CH2)2NH—CPP, —C(O)(CH2)2NHC(O)(CH2)5NH—CPP, —C(O)CH2NH—CPP, and —C(O)CH(pyrrolidin-2-yl)NH—CPP wherein the CPP is attached to the linker moiety by an amide bond at the CPP carboxy terminus, with the proviso that one instance of G is present, and
- wherein the nucleobase sequence comprises a targeting sequence that is complementary to a Pseudomonas aeruginosa mRNA that encodes RpsJ, LpxC, FabG, AcpP, RpmB, WaaC, MraY, MurC, AccA, LpxA, LpxB, WaaG, WaaA, WaaF, MurB, MurE, AccB, FabZ, MurF, MurG, or AmpR.
21 more elements
(canceled)
(canceled)
A method of treating a Pseudomonas aeruginosa infection, comprising administering to a patient in need thereof an effective amount of a composition comprising a compound of formula (I):
- or a pharmaceutically acceptable salt thereof, wherein:
- each Nu is a nucleobase which taken together forms a nucleobase sequence;
- Z is an integer from 8 to 38;
- T is selected from OH and a moiety of the formula:
- wherein:
- each R4 is independently selected from H and C1-C6 alkyl, and
- R5 is selected from an electron pair and H, and
- R6 is selected from —N(R7)CH2C(O)NH2, and a moiety of the formula:
- wherein:
- R7 is selected from H and C1-C6 alkyl;
- and
- R8 is selected from G, —C(O)—R9, acyl, trityl, and 4-methoxytrityl,
- wherein:
- R9 is of the formula —(O-alkyl)y-OH wherein y is an integer from 3 to 10 and each of the y alkyl groups is independently selected from C2-C6 alkyl optionally containing one or more intervening oxygen radicals;
- each instance of R1 is —N(R10)2R11 wherein each R10 is independently C1-C6 alkyl, and R11 is selected from an electron pair and H;
- R2 is selected from the group consisting of H, G, acyl, trityl, 4-methoxytrityl, and a moiety of the formula:
- wherein,
- L is selected from —C(O)(CH2)6C(O)— and —C(O)(CH2)2S2(CH2)2C(O)—;
- and
- each R12 is of the formula —(CH2)2OC(O)N(R26)2 wherein each R26 is of the formula (CH2)6NHC(═NH)NH2;
- and
- R3 is selected from the group consisting of an electron pair, H, and C1-C6 alkyl,
- wherein G is a cell penetrating peptide (“CPP”) and linker moiety selected from the group consisting of —C(O)(CH2)5NH—CPP, —C(O)(CH2)2NH—CPP, —C(O)(CH2)2NHC(O)(CH2)5NH—CPP, —C(O)CH2NH—CPP, and —C(O)CH(pyrrolidin-2-yl)NH—CPP wherein the CPP is attached to the linker moiety by an amide bond at the CPP carboxy terminus, with the proviso that up to one instance of G is present, and
- wherein the nucleobase sequence comprises a targeting sequence that is complementary to a Pseudomonas aeruginosa mRNA that encodes RpsJ, LpxC, FabG, AcpP, RpmB, WaaC, MraY, MurC, AccA, LpxA, LpxB, WaaG, WaaA, WaaF, MurB, MurE, AccB, FabZ, MurF, MurG, or AmpR;
- and
- a pharmaceutically acceptable carrier.
23 more elements
A pharmaceutical combination therapy for the treatment or prevention of a Pseudomonas aeruginosa infection in a patient in need thereof, comprising:
- a compound of formula (I):
- or a pharmaceutically acceptable salt thereof, wherein:
- each Nu is a nucleobase which taken together forms a nucleobase sequence;
- Z is an integer from 8 to 38;
- T is selected from OH and a moiety of the formula:
- wherein:
- each R4 is independently selected from H and C1-C6 alkyl, and
- R5 is selected from an electron pair and H, and
- R6 is selected from —N(R7)CH2C(O)NH2, and a moiety of the formula:
- wherein:
- R7 is selected from H and C1-C6 alkyl;
- and
- R8 is selected from G, —C(O)—R9, acyl, trityl, and 4-methoxytrityl,
- wherein:
- R9 is of the formula —(O-alkyl)y-OH wherein y is an integer from 3 to 10 and each of the y alkyl groups is independently selected from C2-C6 alkyl optionally containing one or more intervening oxygen radicals;
- each instance of R1 is —N(R10)2R11 wherein each R10 is independently C1-C6 alkyl, and R11 is selected from an electron pair and H;
- R2 is selected from the group consisting of H, G, acyl, trityl, 4-methoxytrityl, and a moiety of the formula:
- wherein,
- L is selected from —C(O)(CH2)6C(O)— and —C(O)(CH2)2S2(CH2)2C(O)—;
- and
- each R12 is of the formula —(CH2)2OC(O)N(R26)2 wherein each R26 is of the formula (CH2)6NHC(═NH)NH2;
- and
- R3 is selected from the group consisting of an electron pair, H, and C1-C6 alkyl,
- wherein G is a cell penetrating peptide (“CPP”) and linker moiety selected from the group consisting of —C(O)(CH2)5NH—CPP, —C(O)(CH2)2NH—CPP, —C(O)(CH2)2NHC(O)(CH2)5NH—CPP, —C(O)CH2NH—CPP, and —C(O)CH(pyrrolidin-2-yl)NH—CPP wherein the CPP is attached to the linker moiety by an amide bond at the CPP carboxy terminus, with the proviso that up to one instance of G is present, and
- wherein the nucleobase sequence comprises a targeting sequence that is complementary to a Pseudomonas aeruginosa mRNA that encodes RpsJ, LpxC, FabG, AcpP, RpmB, WaaC, MraY, MurC, AccA, LpxA, LpxB, WaaG, WaaA, WaaF, MurB, MurE, AccB, FabZ, MurF, MurG, or AmpR;
- and
- a second compound selected from the group consisting of polymyxin E (PME), polymyxin B (PMB), polymyxin B nonapeptide (PMBN), polymyxin E nonapeptide, a pharmaceutically acceptable salt of any of the foregoing, and combinations thereof
24 more elements
Dependencies are inferred from the claim text.